Peter Little

Fenofibrate modifies human vascular smooth muscle proteoglycans and reduces lipoprotein binding

Publisher: Springer Science and Business Media LLC

Date: 12-2004

DOI: 10.1007/S00125-004-1588-Z

Abstract: Vascular disease in type 2 diabetes is associated with an up-regulation of atherogenic growth factors, which stimulate matrix synthesis including proteoglycans. We have examined the direct actions of fenofibrate on human vascular smooth muscle cells (VSMCs) and have specifically investigated proteoglycan synthesis and binding to LDL. Proteoglycans synthesised by human VSMCs treated with fenofibrate (30 micromol/l) were assessed for binding to human LDL using a gel mobility shift assay, metabolically labelled with [(35)S]-sulphate and quantitated by cetylpyridinium chloride. They were then assessed for electrophoretic mobility by SDS-PAGE, for size by gel filtration, for sulphation pattern by fluorophore-assisted carbohydrate electrophoresis, and for glycosaminoglycan (GAG) composition by enzyme digestion. Proteoglycans synthesised in the presence of fenofibrate showed an increase in the half-maximum saturation concentration of LDL from 36.8+/-12.4 microg/ml to 77.7+/-17 microg/ml under basal conditions, from 24.9+/-4.6 microg/ml to 39.1+/-6.1 microg/ml in the presence of TGF-beta1, and from 9.5+/-4.4 microg/ml to 31.1+/-3.4 microg/ml in the presence of platelet-derived growth factor/insulin. Fenofibrate treatment in the presence of TGF-beta1 inhibited the incorporation of [(35)S]-sulphate into secreted and cell-associated proteoglycans synthesised by human VSMCs by 59.2% (p<0.01) and 39.8% (p<0.01) respectively. The changes in sulphate incorporation following treatment with fenofibrate were associated with a concentration-related increase in the electrophoretic mobility due to a reduction in GAG length. There was no change in the sulphation pattern however, there was an alteration in the disaccharide composition of the GAGs. Fenofibrate modifies the structure of vascular proteoglycans by reducing the length of the GAG chains and GAG composition, resulting in reduced binding to human LDL, a mechanism which may lead to a reduction of atherosclerosis and cardiovascular disease in people with diabetes treated with fenofibrate.

Amiloride analogues cause endothelium‐dependent relaxation in the canine coronary artery in vitro: possible role of Na⁺/Ca²⁺ exchange

Publisher: Wiley

Date: 09-1988

DOI: 10.1111/J.1476-5381.1988.TB16549.X

Abstract: 1. A number of amiloride analogues were used to test the proposal that Na+/Ca2+ exchange may play a role in the secretion of endothelium-derived relaxing factor (EDRF). The analogues used were those substituted on either the 5-amino group or the terminal guanidino nitrogen atom. The former block both Na+/Ca2+ and Na+/H+ exchange whilst the latter block the Na+ channel and the Na+/Ca2+ exchange. 2. Both series of compounds caused relaxation in isolated rings of dog coronary artery (EC50 values, 1-10 microM) presumably due to release of EDRF since removal of endothelium greatly attenuated the response. 3. Amiloride (1-100 microM) had little effect on either endothelium-intact or denuded arteries. 4. The guanidino substituted analogues also appeared to block selectively the relaxation response to acetylcholine in the coronary artery, independently of their EDRF-releasing activity. 5. It is proposed that endothelial cells have an active Na+/Ca2+ exchange operating in the forward mode to extrude Ca2+. This mechanism may be important in the control of EDRF release.

Rapid regulation of adrenomedullin in metabolically compromised vascular smooth muscle cells

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-1999

DOI: 10.1097/00004872-199917030-00010

Abstract: The prepro-adrenomedullin gene encodes the biologically active peptide adrenomedullin, which acts as a potent vasodilator as well as a modulator of vascular smooth muscle cell growth. We investigated the question of whether adrenomedullin is regulated in response to metabolic perturbations in vascular smooth muscle. Acute inhibition of glycolysis, leading to partial depletion of cellular ATP, was produced in cultured rat aortic vascular smooth muscle cells by replacing glucose with 2-deoxyglucose. Solution hybridization/RNase protection analysis was used to quantitate changes in expression of the prepro-adreno-medullin messenger RNA and a specific radioimmunoassay was used to assess levels of secreted adrenomedullin. Acute incubation of rat aortic vascular smooth muscle cells with 2-deoxyglucose caused a rapid and sustained induction of low basal levels of adrenomedullin messenger RNA, which reached twice the control levels by 1 h and four times control levels by 6 h. The induction of adrenomedullin messenger RNA expression was dependent upon de-novo gene transcription and was reversed by the re-introduction of glucose. Despite the sustained increase in adrenomedullin messenger RNA, secretion of immunoreactive-adrenomedullin from vascular smooth muscle cells was reduced by as much as 75% and paralleled the inhibition of radiolabeled amino acid incorporation into protein during glycolytic inhibition both parameters recovered towards control levels following re-introduction of glucose. The rapid and reversible activation of the adrenomedullin gene and inhibition of adrenomedullin peptide release in response to metabolic inhibition suggest that adrenomedullin represents a novel localized mechanism that may modulate regional blood flow and vascular smooth muscle cell proliferation in response to perturbations of normal metabolism.

Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1

Publisher: Elsevier BV

Date: 02-2014

DOI: 10.1194/JLR.M040394

Changing environment of hyperglycemia in pregnancy: Gestational diabetes and diabetes mellitus in pregnancy

Publisher: Wiley

Date: 26-04-2018

DOI: 10.1111/1753-0407.12660

Abstract: The diagnosis and treatment of gestational diabetes mellitus (GDM) have been in a state of flux since the World Health Organization accepted and endorsed the International Diabetes and Pregnancy Study Group's diagnostic pathway and criteria in 2013. These new diagnostic criteria identify an increasing number of women at risk of hyperglycemia in pregnancy (HGiP). Maternal hyperglycemia represents a significant risk to the mother and fetus, in both the short and long term. Controversially, metformin use for the treatment of GDM is increasing in Australia. This article identifies the multiple and varied presentations of HGiP, of which GDM is the most commonly encountered. The degree of maternal hyperglycemia experienced affects the outcomes for both the mother and neonate, and specific diagnosis determines the appropriate treatment for the pregnancy. Given the increasing incidence of women with dysglycemia and those developing HGiP, this is an important area for research and clinical attention for all health professionals.

Imidazole derivatives as inhibitors of cytochrome P-450-dependent oxidation and activators of epoxide hydrolase in hepatic microsomes from a marine fish

Publisher: Elsevier BV

Date: 10-1981

DOI: 10.1016/0006-2952(81)90432-9

Abstract: Increasing utilization of solar energy is an effective strategy to tackle our energy and energy-related environmental issues. Both solar photocatalysis (PC) and solar photovoltaics (PV) have high potential to develop technologies of many practical applications. Substantial research efforts are devoted to enhancing visible light activation of the photoelectrocatalytic reactions by various modifications of nanostructured semiconductors. This review paper emphasizes the recent advancement in material modifications by means of the promising localized surface plasmonic resonance (LSPR) mechanisms. The principles of LSPR and its effects on the photonic efficiency of PV and PC are discussed here. Many research findings reveal the promise of Au and Ag plasmonic nanoparticles (NPs). Continual investigation for increasing the stability of the plasmonic NPs will be fruitful.

Glucosamine inhibits the synthesis of glycosaminoglycan chains on vascular smooth muscle cell proteoglycans by depletion of ATP

Publisher: Informa UK Limited

Date: 2008

DOI: 10.1080/13813450802033909

Abstract: Glucosamine via GlcNAc is a precursor for the synthesis of glycosaminoglycan (GAG) chains on proteoglycans. We previously found that proteoglycans synthesized and secreted by vascular smooth muscle cells (VSMC) in the presence of supplementary glucosamine had GAG of decreased not increased size. We investigated the possibility that the inhibition of GAG chains synthesis on proteoglycans might be related to cellular ATP depletion. Confluent primate VSMCs were exposed to glucosamine, azide, or 2-deoxyglucose (2-DG). Each of these agents depleted cell ATP content by 25-30%. All agents decreased (35)S-SO(4) incorporation and reduced the size of the proteoglycans, decorin and biglycan as assessed by SDS-PAGE. On withdrawal of the glucosamine, azide or 2-DG ATP levels and proteoglycan synthesis returned towards baseline values. Glucosamine decreased glucose uptake and consumption suggesting that ATP depletion was due preferential phosphorylation of glucosamine over glucose. Thus, glucosamine inhibition of proteoglycan synthesis is due, at least in part, to depletion of cellular ATP content.

Desensitization of the alpha1 adrenoceptor system in vascular smooth muscle

Publisher: Elsevier BV

Date: 04-1984

DOI: 10.1016/0006-2952(84)90527-6

Abstract: The purpose of this study was to evaluate the response of estrogen target cells to a series of isoflavone glucosides and aglycones from Genista halacsyi Heldr. The methanolic extract of aerial parts of this plant was processed using fast centrifugal partition chromatography, resulting in isolation of four archetypal isoflavones (genistein, daidzein, isoprunetin, 8-C-β-D-glucopyranosyl-genistein) and ten derivatives thereof. 7-O-β-D-glucopyranosyl-genistein and 7,4΄-di-O-β-D-glucopyranosyl-genistein were among the most abundant constituents of the isolate. All fourteen, except genistein, displayed low binding affinity for estrogen receptors (ER). Models of binding to ERα could account for the low binding affinity of monoglucosides. Genistein and its glucosides displayed full efficacy in inducing alkaline phosphatase (AlkP) in Ishikawa cells, proliferation of MCF-7 cells and ER-dependent gene expression in reporter cells at low concentrations (around 0.3 μM). ICI182,780 fully antagonized these effects. The AlkP-inducing efficacy of the fourteen isoflavonoids was more strongly correlated with their transcriptional efficacy through ERα. O-monoglucosides displayed higher area under the dose-response curve (AUC) of AlkP response relative to the AUC of ERα-transcriptional response compared to the respective aglycones. In addition, 7-O-β-D-glucopyranosyl-genistein and 7,4΄-di-O-β-D-glucopyranosyl-genistein displayed estradiol-like efficacy in promoting differentiation of MC3T3-E1 cells to osteoblasts, while genistein was not convincingly effective in this respect. Moreover, 7,4΄-di-O-β-D-glucopyranosyl-genistein suppressed lipopolysaccharide-induced tumor necrosis factor mRNA expression in RAW 264.7 cells, while 7-O-β-D-glucopyranosyl-genistein was not convincingly effective and genistein was ineffective. However, genistein and its O-glucosides were ineffective in inhibiting differentiation of RAW 264.7 cells to osteoclasts and in protecting glutamate-challenged HT22 hippoc al neurons from oxidative stress-induced cell death. These findings suggest that 7-O-β-D-glucopyranosyl-genistein and 7,4΄-di-O-β-D-glucopyranosyl-genistein display higher estrogen-like and/or anti-inflammatory activity compared to the aglycone. The possibility of using preparations rich in O-β-D-glucopyranosides of genistein to substitute for low-dose estrogen in formulations for menopausal symptoms is discussed.

Troglitazone Stimulates Repair of the Endothelium and Inhibits Neointimal Formation in Denuded Rat Aorta

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 05-2003

DOI: 10.1161/01.ATV.0000069210.46539.0D

Abstract: Objective— Vascular endothelium is emerging as a therapeutic target for atherosclerotic macrovascular disease in diabetes using oral hypoglycemic agents with pleiotropic actions. We have addressed whether the thiazolidinedione troglitazone has effects on the endothelial cell response to injury in rat aorta and its interaction with the growth response of underlying vascular smooth muscle. Methods and Results— Repair of rat aorta after balloon catheter injury in troglitazone-treated (400 mg/kg per day by mouth) rats showed early acceleration of reendothelialization and late reduction in neointima formation. Complementary in vitro studies showed that troglitazone dose-dependently inhibited migration and proliferation of cultured macrovascular endothelial and vascular smooth muscle cells in low-glucose (5 mmol/L) and high-glucose (25 mmol/L) media. However, in endothelial cells, the inhibitory response at low ( μmol/L) troglitazone concentrations resulted from direct inhibition of proliferation, whereas inhibition at higher (10 μmol/L) concentrations was secondary to apoptosis and necrosis. Additional studies indicated a concentration-specific activity of troglitazone to protect endothelial cells from apoptosis. Conclusions— Troglitazone had effects consistent with maintenance of vascular integrity and protection against mechanisms of atherosclerosis and restenosis, which may arise from a concentration-specific effect to reduce high rates of apoptosis occurring in cultured cells and repairing vessels.

Intracellular pH in human arterial smooth muscle. Regulation by Na+/H+ exchange and a novel 5-(N-ethyl-N-isopropyl)amiloride-sensitive Na(+)- and HCO3(-)-dependent mechanism.

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-1990

DOI: 10.1161/01.RES.67.4.814

Abstract: We investigated in a physiological salt solution (PSS) containing HCO3- the intracellular pH (pHi) regulating mechanisms in smooth muscle cells cultured from human internal mammary arteries, using the pH-sensitive dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein (BCECF) and 22Na+ influx rates. The recovery of pHi from an equivalent intracellular acidosis was more rapid when the cells were incubated in CO2/HCO3(-)-buffered PSS than in HEPES-buffered PSS. Recovery of pHi was dependent on extracellular Na+ (Km, 13.1 mM) however, it was not attenuated by 4-acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic acid (SITS), indicating the absence of SITS-sensitive HCO3(-)-dependent mechanisms. Recovery instead appeared mostly dependent on processes sensitive to 5-(N-ethyl-N-isopropyl)amiloride (EIPA), indicating the involvement of Na+/H+ exchange and a previously undescribed EIPA-sensitive Na(+)- and HCO3(-)-dependent mechanism. Differentiation between this HCO3(-)-dependent mechanism and Na+/H+ exchange was achieved after depletion of cellular ATP. Under these conditions, the NH4Cl-induced 22Na+ influx rate stimulated by intracellular acidosis was markedly attenuated in HEPES-buffered PSS but not in CO2/HCO3(-)-buffered PSS. EIPA also appeared to inhibit the two mechanisms differentially. In HEPES-buffered PSS containing 20 mM Na+, the EIPA inhibition curve for the intracellular acidosis-induced 22Na+ influx was monophasic (IC50, 39 nM), whereas in an identical CO2/HCO3(-)-buffered PSS, the inhibition curve exhibited biphasic characteristics (IC50, 37.3 nM and 312 microM). Taken together, the results indicate that Na+/H+ exchange and a previously undescribed EIPA-sensitive Na(+)- and HCO3(-)-dependent mechanism play an important role in regulating the pHi of human vascular smooth muscle. The involvement of the latter mechanism depends on the severity of the intracellular acidosis, varying from approximately 25% in severe intracellular acidosis up to 50% at lesser, more physiological, levels of induced acidosis.

Diabetes induces Na/H exchange activity and hypertrophy of rat mesenteric but not basilar arteries

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1016/J.DIABRES.2005.03.038

Abstract: Experimental hyperglycemia produces a marked hypertrophic response in rat mesenteric arteries, accompanied by activation of Na/H exchange (NHE) in medial smooth muscle. This study asked if other vascular beds are similarly affected by examining the hypertrophic and NHE response of the basilar artery. Sections of mesenteric and basilar arteries from adult rats were analysed by standard morphometric techniques at 1 and 3 weeks after streptozotocin injection. NHE activity was assessed as changes in intracellular pH in isolated intact vessels using concurrent myography and fluorescence spectroscopy. Mesenteric arteries showed a significant increase in lumenal (47%), medial (51%) and adventitial (17%) area. In contrast, these parameters were not increased in basilar arteries from the same set of animals. Maximal NHE activity was significantly increased at 1 week (24%) and 3 weeks (20%) in mesenteric arteries, but in basilar arteries there was no change in basal intracellular pH, maximal NHE activity or kinetic properties of the transporter. NHE plays a central role in vascular changes in diabetes. As the mesenteric hypertrophy is amenable to therapeutic intervention these findings add further to the potential of NHE as a therapeutic target for ameliorating vascular disease in diabetes.

Curcumin Inhibits Lysophosphatidic Acid Mediated MCP-1 Expression via Blocking ROCK Signalling

Publisher: MDPI AG

Date: 16-04-2021

DOI: 10.3390/MOLECULES26082320

Abstract: Curcumin is a natural compound that has been widely used as a food additive and medicine in Asian countries. Over several decades, erse biological effects of curcumin have been elucidated, such as anti-inflammatory and anti-oxidative activities. Monocyte chemoattractant protein-1 (MCP-1) is a key inflammatory marker during the development of atherosclerosis, and curcumin blocks MCP-1 expression stimulated by various ligands. Hence, we studied the action of curcumin on lysophosphatidic acid (LPA) mediated MCP-1 expression and explored the specific underlying mechanisms. In human vascular smooth muscle cells, LPA induces Rho-associated protein kinase (ROCK) dependent transforming growth factor receptor (TGFBR1) transactivation, leading to glycosaminoglycan chain elongation. We found that LPA also signals via the TGFBR1 transactivation pathway to regulate MCP-1 expression. Curcumin blocks LPA mediated TGFBR1 transactivation and subsequent MCP-1 expression by blocking the ROCK signalling. In the vasculature, ROCK signalling regulates smooth muscle cell contraction, inflammatory cell recruitment, endothelial dysfunction and vascular remodelling. Therefore, curcumin as a ROCK signalling inhibitor has the potential to prevent atherogenesis via multiple ways.

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

Publisher: Elsevier BV

Date: 09-2023

DOI: 10.1016/J.APSB.2023.09.014

SPONTANEOUS OSCILLATIONS IN CYTOPLASMIC FREE CALCIUM CONCENTRATION IN VASCULAR SMOOTH MUSCLE: A POTENTIAL MECHANISM ASSOCIATED WITH MYOGENIC TONE

Publisher: Wiley

Date: 04-1988

DOI: 10.1111/J.1440-1681.1988.TB01073.X

Abstract: 1. The cytoplasmic free calcium concentration was monitored in primary rat aortic smooth muscle cells, grown in culture and serum-deprived for 24-48 h, with the calcium sensitive fluoroprobe, Fura-2. 2. In the absence of external stimuli, spontaneous increases in the cytoplasmic free calcium concentration were observed which averaged 60 +/- 11 nmol/l and lasted approximately 30 s. 3. The calcium transients were in part dependent on intracellular calcium and were abolished when the temperature was lowered to 10 degrees C. 4. It is concluded that vascular smooth muscle cells have an inherent ability to initiate spontaneous transient increases in cytoplasmic free calcium concentration via membrane calcium channels.

Lipid: Extracellular Matrix Interactions as Therapeutic Targets in the Atherosclerosis of Diabetes

Publisher: Springer New York

Date: 17-07-2013

DOI: 10.1007/978-1-4614-7554-5_11

The status of radioimmunotherapy in CD20+ non-Hodgkin’s lymphoma

Publisher: Springer Science and Business Media LLC

Date: 29-05-2014

DOI: 10.1007/S11523-014-0324-Y

Abstract: Rituximab, the CD20-directed antibody, has become a standard component of treatment regimens for patients with B cell non-Hodgkin's lymphoma (NHL). The use of rituximab has resulted in greatly improved response and survival rates with less toxicity relative to standard chemotherapeutic regimes. However, relapse and recurrence is common, particularly in indolent varieties which remain incurable, requiring alternate therapeutic options. The subsequent coupling of β-emitting isotopes such as (131)I and (90)Y to anti-CD20 monoclonal antibodies (mAbs), including rituximab, has been steadily growing over the last decade and demonstrates even greater therapeutic efficacy with more durable responses. (177)Lutetium-labelled rituximab offers a number of convenient advantages over (131)I and (90)Y anti-CD20 mAbs for treatment of NHL, and a number of alpha-emitting isotopes lie at the frontier of consolidation therapy for residual, micrometastatic disease.

The Atypical Antipsychotic Agent, Clozapine, Protects Against Corticosterone-Induced Death of PC12 Cells by Regulating the Akt/FoxO3a Signaling Pathway

Publisher: Springer Science and Business Media LLC

Date: 13-05-2016

DOI: 10.1007/S12035-016-9904-4

Abstract: Schizophrenia is one of the most severe psychiatric disorders. Increasing evidence implicates that neurodegeneration is a component of schizophrenia pathology and some atypical antipsychotics are neuroprotective and successful in slowing the progressive morphological brain changes. As an antipsychotic agent, clozapine has superior and unique effects, but the intracellular signaling pathways that mediate clozapine action remain to be elucidated. The phosphatidylinositol-3-kinase rotein kinase B/Forkhead box O3 (PI3K/Akt/FoxO3a) pathway is crucial for neuronal survival. However, little information is available regarding this pathway with clozapine. In the present study, we investigated the protective effect of clozapine on the PC12 cells against corticosterone toxicity. Our results showed that corticosterone decreases the phosphorylation of Akt and FoxO3a, leading to the nuclear localization of FoxO3a and the apoptosis of PC12 cells, while clozapine concentration dependently protected PC12 cells against corticosterone insult. Pathway inhibitors studies displayed that the protective effect of clozapine was reversed by LY294002 and wortmannin, two PI3K inhibitors, or Akt inhibitor VIII although several other inhibitors had no effect. The shRNA knockdown results displayed that downregulated Akt1 or FoxO3a attenuated the protective effect of clozapine. Western blot analyses revealed that clozapine induced the phosphorylation of Akt and FoxO3a by the PI3K/Akt pathway and reversed the reduction of the phosphorylated Akt and FoxO3a and the nuclear translocation of FoxO3a evoked by corticosterone. Together, our data indicates that clozapine protects PC12 cells against corticosterone-induced cell death by modulating activity of the PI3K/Akt/FoxO3a pathway.

TGF-β stimulates biglycan core protein synthesis but not glycosaminoglycan chain elongation via Akt phosphorylation in vascular smooth muscle

Publisher: Informa UK Limited

Date: 13-09-2011

DOI: 10.3109/08977194.2011.615747

Abstract: Transforming growth factor-β (TGF-β) can mediate proteoglycan synthesis via Smad and non-Smad signalling pathways in vascular smooth muscle (VSM). We investigated whether TGF-β-mediated proteoglycan synthesis is via PI3K/Akt. TGF-β induced a rapid phosphorylation of Akt that continued upto 4 h. Akt phosphorylation was blocked by Akt1/2 inhibitor SN30978 however, it did not block Smad2 phosphorylation at either the carboxy or linker regions indicating that TGF-β-mediated Akt phosphorylation is independent of Smad2 signalling. The role of Akt in TGF-β-mediated proteoglycan synthesis was investigated. Treatment with SN30978 showed a concentration-dependent decrease in TGF-β-mediated [(35)S]-sulphate and [(35)S]-Met/Cys incorporation into secreted proteoglycans however, SDS-PAGE showed no change in biglycan size. In TGF-β-treated cells, biglycan mRNA levels increased by 40-100% in 24 h and was significantly blocked by SN30978. Our findings demonstrate that Akt is a downstream signalling component of TGF-β-mediated biglycan core protein synthesis but not glycosaminoglycan chain hyper-elongation in VSM.

Role of Ca ²⁺ in Metabolic Inhibition–Induced Norepinephrine Release in Rat Brain Synaptosomes

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 02-1997

DOI: 10.1161/01.RES.80.2.179

Abstract: Ischemia and simulated ischemic conditions induce enhanced release of norepinephrine (NE) in the brain and the heart. Although studies with neuronal preparations demonstrated a rise in [Ca 2+ ] i under energy-depleted conditions, such release of NE in the heart appears to be predominantly Ca 2+ independent. Since Ca 2+ overload occurs in ischemia or energy depletion and since a rise in [Ca 2+ ] i triggers exocytosis without membrane depolarization, we tested the possibility, using brain synaptosomes, that increased NE release could be, at least in part, a consequence of raised [Ca 2+ ] i . Brain synaptosomes were incubated with Krebs-Henseleit medium, and ischemia was mimicked by treatment with metabolic inhibitors. NE content in incubation medium (supernatant) and synaptosomes was analyzed chromatographically. Treatment with metabolic inhibitors reduced ATP content by 75% and increased [Ca 2+ ] i by more than fourfold within minutes. Metabolic inhibition elicited NE release, which started within 10 minutes and reached a maximum after 30 minutes, with a corresponding 55% reduction in synaptosomal NE content after 40 minutes. NE release, together with a marked increase in [Ca 2+ ] i , was also induced in energy-depleted synaptosomes by Ca 2+ repletion after incubation with the Ca 2+ -free medium. Effects on NE release of various interventions to prevent Ca 2+ overload were tested. Omission of Ca 2+ from the incubation medium or loading synaptosomes with the Ca 2+ chelator BAPTA-AM (20 and 100 μmol/L) prevented NE release, indicating a Ca 2+ -dependent mechanism. Inhibition of Ca 2+ channels with ω-conotoxin, cadmium, or nifedipine had no effect on NE release during energy depletion. In contrast, nickel and 3,4-dichlorobenzamil, Na + -Ca 2+ exchange inhibitors, dose-dependently inhibited NE release. In conclusion, this study provides evidence that under energy-depleted conditions, Ca 2+ overload in synaptosomes of noradrenergic neurons from the brain is an important mechanism for the enhanced release of NE and that a reversal of Na + -Ca 2+ exchange may be the key pathway leading to intraneuronal Ca 2+ overload.

Tanshinone II-A attenuates and stabilizes atherosclerotic plaques in Apolipoprotein-E knockout mice fed a high cholesterol diet

Publisher: Elsevier BV

Date: 11-2011

DOI: 10.1016/J.ABB.2011.08.006

Abstract: Tanshinone II-A (Tan), a bioactive diterpene isolated from Salvia miltiorrhiza Bunge (Danshen), possesses anti-oxidant and anti-inflammatory activities. The present study investigated whether Tan can decrease and stabilize atherosclerotic plaques in Apolipoprotein-E knockout (ApoE(-/-)) mice maintained on a high cholesterol diet (HCD). Six week-old mice challenged with a HCD were randomly assigned to 4 groups: (a) C57BL/6J (b) ApoE(-/-) (c) ApoE(-/-)+Tan-30 (30 mg/kg/d) (d) ApoE(-/-)+Tan-10 (10mg/kg/d). After 16 weeks of intervention, Tan treated mice showed decreased atherosclerotic lesion size in the aortic sinus and en face aorta. Furthermore, immunohistochemical analysis revealed that Tan rendered the lesion composition a more stable phenotype as evidenced by reduced necrotic cores, decreased macrophage infiltration, and increased smooth muscle cell and collagen contents. Tan also significantly reduced in situ superoxide anion production, aortic expression of NF-κB and matrix metalloproteinase-9 (MMP-9). In vitro treatment of RAW264.7 macrophages with Tan significantly suppressed oxidized LDL-induced reactive oxygen species production, pro-inflammatory cytokine (IL-6, TNF-α, MCP-1) expression, and MMP-9 activity. Tan attenuates the development of atherosclerotic lesions and promotes plaque stability in ApoE(-/-) mice by reducing vascular oxidative stress and inflammatory response. Our findings highlight Tan as a potential therapeutic agent to prevent atherosclerotic cardiovascular diseases.

Poly(ADP‐ribose) Polymerase 1 (PARP1) in Atherosclerosis: From Molecular Mechanisms to Therapeutic Implications

Publisher: Wiley

Date: 03-09-2013

DOI: 10.1002/MED.21300

Abstract: Poly(ADP-ribosyl)ation reactions, carried out by poly(ADP-ribose) polymerases (PARPs/ARTDs), are reversible posttranslational modifications impacting on numerous cellular processes (e.g., DNA repair, transcription, metabolism, or immune functions). PARP1 (EC 2.4.2.30), the founding member of PARPs, is particularly important for drug development for its role in DNA repair, cell death, and transcription of proinflammatory genes. Recent studies have established a novel concept that PARP1 is critically involved in the formation and destabilization of atherosclerotic plaques in experimental animal models and in humans. Reduction of PARP1 activity by pharmacological or molecular approaches attenuates atherosclerotic plaque development and enhances plaque stability as well as promotes the regression of pre-established atherosclerotic plaques. Mechanistically, PARP1 inhibition significantly reduces monocyte differentiation, macrophage recruitment, Sirtuin 1 (SIRT1) inactivation, endothelial dysfunction, neointima formation, foam cell death, and inflammatory responses within plaques, all of which are central to the pathogenesis of atherosclerosis. This article presents an overview of the multiple roles and underlying mechanisms of PARP1 activation (poly(ADP-ribose) accumulation) in atherosclerosis and emphasizes the therapeutic potential of PARP1 inhibition in preventing or reversing atherosclerosis and its cardiovascular clinical sequalae.

Imatinib inhibits vascular smooth muscle proteoglycan synthesis and reduces LDL binding in vitro and aortic lipid deposition in vivo

Publisher: Wiley

Date: 14-09-2009

DOI: 10.1111/J.1582-4934.2009.00902.X

Determination of dose enhancement caused by gold-nanoparticles irradiated with proton, X-rays (kV and MV) and electron beams, using alanine/EPR dosimeters

Publisher: Elsevier BV

Date: 11-2015

DOI: 10.1016/J.RADMEAS.2015.09.008

Plasma noradrenaline kinetics in humans

Publisher: Elsevier BV

Date: 09-1984

DOI: 10.1016/0165-1838(84)90071-7

Abstract: Recently developed radiotracer methods for measuring the overall rate of release of noradrenaline to plasma, for the body as a whole, can be used to estimate 'total sympathetic nervous system activity' in humans. These techniques find application in clinical studies of sympathetic nervous physiology and pharmacology. The inherent weakness of any biochemical test of global sympathetic tone such as this lies in the fact that sympathetic nervous system responses typically show regional differentiation. Biochemical indices of overall sympathetic activity are insufficiently discriminating to delineate patterns of sympathetic nervous response, representing instead an algebraic sum of all regional increases or decreases in sympathetic tone. Modification of the whole-body radiotracer methodology enables organ-specific sympathetic nervous system activity to be estimated, from measurements of regional release of noradrenaline to plasma. This should facilitate investigation of possible sympathetic pathophysiology in disease states. Illustrative of potential application of the method are preliminary findings of increased renal sympathetic nervous tone in young patients with essential hypertension, and of selective activation of sympathetic nerves to the kidney by diuretics.

The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

Publisher: Springer Science and Business Media LLC

Date: 12-11-2015

DOI: 10.1007/S00018-014-1775-0

Abstract: G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the "triple membrane bypass" pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier.

The emerging role of Metformin in Gestational Diabetes Mellitus

Publisher: Wiley

Date: 24-03-2017

DOI: 10.1111/DOM.12893

Abstract: Metformin use during pregnancy is controversial and there is disparity in the acceptance of metformin treatment in women with gestational diabetes mellitus (GDM) in Australia. Despite short term maternal and neonatal safety measures, the placental transfer of metformin during GDM treatment and the absence of long-term safety data in offspring has regulators and prescribers cautious about its use. To determine the current role in GDM management, this literature review describes the physiological changes that occur in GDM and other forms of diabetes in pregnancy (DIP) and international changes in guidelines for GDM diagnosis. Management options are considered, with a focus on the evolving evidence for metformin, its mechanism of action, the maternal, foetal and neonatal outcomes associated with its use and benefit vs risk when compared with the current gold standard, insulin. Investigation reveals a favourable balance of evidence to support the safety and long-term benefits, to mother and child, of using metformin as an alternate to insulin for treatment of GDM. Recent findings of the gastrointestinal-directed action of metformin are at least as important as the hepatic effect and the availability of a novel delayed-release metformin dose form to exploit this new information provides a product and therapeutic strategy ideally suited to the use of metformin in GDM.

Diabetes-Induced Vascular Hypertrophy Is Accompanied by Activation of Na ⁺ -H ⁺ Exchange and Prevented by Na +

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 08-12-2000

DOI: 10.1161/01.RES.87.12.1133

Abstract: Abstract —Vascular disease often involves vessel hypertrophy with underlying cellular hypertrophy or hyperplasia. Experimental diabetes stimulates hypertrophy of the rat mesenteric vasculature, and we investigated the hypothesis that this hypertrophy is associated with activation of Na + -H + exchange (NHE) activity. We measured the NHE activity in isolated, intact blood vessels from control and streptozotocin-induced diabetic adult rats using concurrent myography and fluorescence spectroscopy. The role of inhibiting NHE activity in preventing the development of the mesenteric hypertrophy in streptozotocin-diabetic rats was investigated by administration of cariporide (100 mg/kg body weight per day in 3 doses by gavage) after induction of diabetes and subsequently determining vessel weight and structure. The weight of the mesenteric vasculature was not increased 1 week after streptozotocin treatment but was significantly increased by an average of 56% at 3 weeks. NHE activity in mesenteric arteries showed an enhanced maximal velocity ( V max ) in diabetic vessels at 1 and 3 weeks (0.246±0.006 and 0.238±0.007 versus 0.198±0.007 pH U/min) with no change in the apparent K m . Moreover, NHE-1 mRNA in mesenteric arterioles at 3 weeks after streptozotocin treatment was increased by % (55.8±6.4 versus 91.3±12.3 fg). Administration of cariporide significantly reduced mesenteric vascular weight, the wall/lumen ratio, and mesenteric extracellular matrix accumulation in the diabetic animals. Our study shows that diabetes in vivo correlates with elevated NHE activity and mRNA in the mesenteric vasculature and furthermore that inhibition of this system prevents the hypertrophic response. These data suggest that NHE may be a target for therapeutic modulation of vascular changes in diabetes.

Cellular and Molecular Pathology of Age-Related Macular Degeneration: Potential Role for Proteoglycans

Publisher: Hindawi Limited

Date: 2016

DOI: 10.1155/2016/2913612

Abstract: Age-related macular degeneration (AMD) is a retinal disease evident after the age of 50 that damages the macula in the centre of retina. It leads to a loss of central vision with retained peripheral vision but eventual blindness occurs in many cases. The initiation site of AMD development is Bruch’s membrane (BM) where multiple changes occur including the deposition of plasma derived lipids, accumulation of extracellular debris, changes in cell morphology, and viability and the formation of drusen. AMD manifests as early and late stage the latter involves cell proliferation and neovascularization in wet AMD. Current therapies target the later hyperproliferative and invasive wet stage whilst none target early developmental stages of AMD. In the lipid deposition disease atherosclerosis modified proteoglycans bind and retain apolipoproteins in the artery wall. Chemically modified trapped lipids are immunogenic and can initiate a chronic inflammatory process manifesting as atherosclerotic plaques and subsequent artery blockages, heart attacks, or strokes. As plasma derived lipoprotein deposits are found in BM in early AMD, it is possible that they arise by a similar process within the macula. In this review we consider aspects of the pathological processes underlying AMD with a focus on the potential role of modifications to secreted proteoglycans being a cause and therefore a target for the treatment of early AMD.

Dihydropyridine Ca2+ channel antagonists inhibit the salvage pathway for DNA synthesis in human vascular smooth muscle cells

Publisher: Elsevier BV

Date: 02-1993

DOI: 10.1016/0922-4106(93)90152-Y

Abstract: We examined the mechanisms by which Ca2+ channel antagonists inhibit the growth of smooth muscle cells by determining their effect on epidermal growth factor (EGF)-stimulated (i) induction of the early signalling gene, c-fos, (ii) incorporation of [3H]thymidine into cells as a measure of DNA synthesis, and (iii) increase in cell number. Verapamil, diltiazem, and the dihydropyridines felodipine, MDL 72892 A-15 (MDL) and nisoldipine had no effect on EGF-stimulated c-fos mRNA induction. Furthermore, only small inhibitory effects were observed on EGF-stimulated increases in cell number felodipine, MDL, and nisoldipine at 0.3 microM inhibited EGF-stimulated cell proliferation by 9, 11, and 15%, respectively. In contrast, the dihydropyridine Ca2+ channel antagonists were found to be potent inhibitors of [3H]thymidine incorporation suggesting that they inhibit DNA synthesis. However, further examination revealed that the potent effects of dihydropyridine Ca2+ channel antagonists on [3H]thymidine incorporation were due not to an effect on incorporation of [3H]thymidine into DNA, but to a marked inhibitory effect on the cellular uptake of [3H]thymidine. Thus, we conclude that the small antiproliferative effects of the dihydropyridine antagonists are predominantly due to their ability to inhibit the activity of the salvage pathway for thymidylate synthesis in human vascular smooth muscle cells.

Lysophosphatidic acid receptor 5 transactivation of TGFBR1 stimulates the mRNA expression of proteoglycan synthesizing genes XYLT1 and CHST3

Publisher: Elsevier BV

Date: 12-2020

DOI: 10.1016/J.BBAMCR.2020.118848

Genistein inhibits PDGF-stimulated proteoglycan synthesis in vascular smooth muscle without blocking PDGFβ receptor phosphorylation

Publisher: Elsevier BV

Date: 09-2012

DOI: 10.1016/J.ABB.2012.05.025

Abstract: The signaling pathways that regulate the synthesis and structure of proteoglycans secreted by vascular smooth muscle cells are potential therapeutic targets for preventing lipid deposition in the early stage of atherosclerosis. PDGF stimulates both core protein expression and elongation of glycosaminoglycan (GAG) chains on proteoglycans. In this study we investigated the effects of the tyrosine kinase inhibitor genistein on PDGF mediated receptor phosphorylation and proteoglycan synthesis in human vascular smooth muscle cells. We demonstrate that genistein does not block phosphorylation of the activation site of the PDGF receptor at Tyr(857) and two other downstream sites Tyr(751) and Tyr(1021). Genistein blocked PDGF-mediated proteoglycan core protein synthesis however it had no effect on GAG chain elongation. These results differ markedly to two other tyrosine kinase inhibitors, imatinib and Ki11502, that block PDGF receptor phosphorylation and PDGF mediated GAG elongation. We conclude that the action of genistein on core protein synthesis does not involve the PDGF receptor and that PDGF mediates GAG elongation via the PDGF receptor.

Insights into cellular signalling by G protein coupled receptor transactivation of cell surface protein kinase receptors

Publisher: Springer Science and Business Media LLC

Date: 06-02-2017

DOI: 10.1007/S12079-017-0375-9

Zinc and cardiovascular disease

Publisher: Elsevier BV

Date: 11-2010

DOI: 10.1016/J.NUT.2010.03.007

Abstract: Zinc is a vital element in maintaining the normal structure and physiology of cells. The fact that it has an important role in states of cardiovascular diseases has been studied and described by several research groups. It appears to have protective effects in coronary artery disease and cardiomyopathy. Intracellular zinc plays a critical role in the redox signaling pathway, whereby certain triggers such as ischemia and infarction lead to release of zinc from proteins and cause myocardial damage. In such states, replenishing with zinc has been shown to improve cardiac function and prevent further damage. Thus, the area of zinc homeostasis is emerging in cardiovascular disease research. The goal of this report is to review the current knowledge and suggest further avenues of research.

Circulating digoxin-like immunoreactivity in renal hypertensive rabbits: lack of modulation by alterations in dietary sodium intake

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-1988

DOI: 10.1097/00004872-198803000-00004

Abstract: We have re-examined digoxin-like immunoreactivity, commonly detected in plasma with antibodies, in order to determine whether it could represent the putative natriuretic factor originally proposed by de Wardener and Clarkson. Experiments were conducted in adult rabbits with two-kidney, two wrapped hypertension and in sham-operated controls. Six weeks after the bilateral renal cellophane wrapping or sham operation, the mean arterial pressure (MAP) was approximately 40 mmHg higher in the wrapped group. At this time the rabbits started a low-, normal- or high-salt diet (1.6, 25.6 and 40.8 mmol Na+/100 g) which continued for 2 weeks. During the final 3 days urinary volume and total sodium content measured in 24-h collections was significantly lowered in the rabbits on the low-salt diet and increased by the high-salt diet (P less than 0.01 for both). This pattern was identical for the normotensive and renal hypertensive rabbits. Digoxin-like immunoreactivity was measured at the beginning and at the end of the 2-week period of the salt study. Immediately before commencing the various salt diets the digoxin-like immunoreactivity, measured as ng digoxin equivalents/ml, was only marginally elevated in the renal hypertensive compared to the normotensive animals (it averaged 94.7 +/- 7.7 and 80.9 +/- 5.9 ng digoxin equivalents/ml, respectively). Neither the low- nor the high-sodium diet affected plasma digoxin-like immunoreactivity in either the normotensive or the renal hypertensive animals (P greater than 0.10). These results indicate that digoxin-like immunoreactivity is present in the plasma of normotensive and renal hypertensive rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Regulation of glycosaminoglycan structure and atherogenesis

Publisher: Springer Science and Business Media LLC

Date: 05-2004

DOI: 10.1007/S00018-004-3389-4

Abstract: Cardiovascular disease is the major cause of premature death in modern society, and its impact is increasing due to rising rates of obesity and type 2 diabetes. Clinical studies based on targeting metabolic abnormalities and biomarkers demonstrate significant benefits, but always an element of disease remains which is resistant to treatment. Recent evidence has strongly implicated an early interaction of atherogenic lipoproteins with vascular matrix proteoglycans as the initiating step in atherogenesis. Expert commentary has pointed to the need for vascular directed therapies to provide reductions in the residual disease component. We propose that the regulation of synthesis and thus structure of glycosaminoglycans on proteoglycans provides a potential pathway to this reduction. We review existing evidence that the vascular synthesis of glycosaminoglycan chains can be regulated in a manner which reduces lipoprotein binding and the potential application of this strategy to attenuation of the current cardiovascular disease pandemic.

Transforming Growth Factor-β1 Regulates the Expression of Ryanodine-Sensitive Ca2+ Oscillations in Cardiac Myocytes

Publisher: Elsevier BV

Date: 10-1994

DOI: 10.1006/BBRC.1994.2513

Abstract: Factors which regulate sarcoplasmic reticulum (SR) gene expression are largely unknown. We investigated whether Transforming Growth Factor-beta 1 (TGF-beta 1) plays a role in the maintenance of Ca2+ handling mechanisms in isolated neonatal rat cardiomyocytes. Myocytes cultured in the presence of serum were found to beat continuously and undergo spontaneous Ca2+ oscillations whereas in the absence of serum the cells lost the ability to undergo cyclical Ca2+ oscillations. The oscillations were restored when serum-free medium was supplemented with TGF-beta 1. Both caffeine-induced Ca2+ elevations and the inhibitory effect of ryanodine on spontaneous activity were also dependent on the continued presence of TGF-beta 1 in its absence these indices of SR function were severely compromised. TGF-beta 1 therefore appears to play a critical role in the maintenance of Ca2+ oscillations in the heart by regulating the expression of the ryanodine-sensitive Ca2+ release mechanism.

Atheroprotective Effects and Molecular Targets of Tanshinones Derived From Herbal Medicine Danshen

Publisher: Wiley

Date: 16-02-2017

DOI: 10.1002/MED.21438

Abstract: Medicinal plant-derived bioactive compounds modulate multiple therapeutic targets in cardiovascular diseases (CVDs), rendering herb-derived phytochemicals effective against one of the major CVDs-atherosclerosis. Danshen (Salvia milthiorriza Bunge) is a Chinese medicine that has been used in cardio- and cerebro-vascular therapeutic remedies in Asian countries for many years. Emerging evidence from cellular, animal, and clinical studies suggests that major lipophilic tanshinones from Danshen can treat atherosclerotic CVDs. In this review, we highlight recent advances in understanding the molecular mechanisms of tanshinones in treating atherosclerosis, ranging from endothelial dysfunction to chronic inflammation. We also overview new molecular targets of tanshinones, including endothelial nitric oxide synthase, AMP-activated protein kinase, ABC transporter A1, heme oxygenase 1, soluble epoxide hydrolase, 11β-hydroxysteroid dehydrogenase, estrogen receptor, and proprotein convertase subtilisin/kexin type 9. Thus, this review provides a new perspective for advancing our understanding of the "ancient" herb Danshen from "modern" biomedical perspectives, supporting the possibility of exploiting tanshinones and derivatives as effective therapeutics against atherosclerosis-related cardiovascular and metabolic diseases.

Endothelin-1 activates ETA receptors on human vascular smooth muscle cells to yield proteoglycans with increased binding to LDL

Publisher: Elsevier BV

Date: 08-2009

DOI: 10.1016/J.ATHEROSCLEROSIS.2009.01.024

Abstract: Lipid retention in the vessel wall by glycosaminoglycan (GAG) chains on chondroitin/dermatan sulfate proteoglycans synthesized by vascular smooth muscle cells (VSMC) have recently been established as an early event in human coronary artery atherosclerosis. GAG structure can be altered by growth factors resulting in enhanced binding to low density lipoprotein (LDL). The aim of this study was to determine if proteoglycans produced by endothelin-1 treated VSMCs had increased binding to human LDL, to examine the effect of endothelin-1 on the synthesis and structure of proteoglycans and to elucidate the signalling pathway. Endothelin-1 stimulated an increase in [(35)S]sulfate and [(3)H]glucosamine incorporation into proteoglycans produced by human VSMC. The increase was due to an increase in GAG chain size assessed by SDS-PAGE and size exclusion chromatography. Increased radiolabel incorporation was inhibited by an ET(A) but not an ET(B) receptor antagonist. Endothelin-1 stimulated an increase in the 6:4 position sulfation ratio on the disaccharides of the GAG chains, an effect that was blocked by bosentan. The EGF receptor antagonist AG1478 did not affect the increase in GAG size mediated by endothelin-1. Inhibition of protein kinase C (PKC) with GF109203X or down regulation by PMA pre-treatment attenuated the effect of endothelin-1 on GAG synthesis. These data demonstrate that endothelin-1 stimulates changes in GAG chain structure that increase binding to LDL. This action of endothelin-1 may represent a new target for the prevention of lipid binding within the vascular wall and the associated complications resulting from this interaction.

Danhong injection in cardiovascular and cerebrovascular diseases: Pharmacological actions, molecular mechanisms, and therapeutic potential

Publisher: Elsevier BV

Date: 2019

DOI: 10.1016/J.PHRS.2018.11.006

Abstract: Cardiovascular and cerebrovascular diseases are the main cause of mortality worldwide, currently with less than optimum therapeutic options. Danhong injection (DHI) is a medicinal preparation based on two eminent Chinese herbal medicines, Salviae Miltiorrhizae (Dan Shen family: Lamiaceae) and Flos Carthami (Hong Hua family: Compositae/Asteraceae). DHI has been mainly used in the clinical therapy of cardiovascular (such as acute coronary syndrome and angina pectoris) and cerebrovascular diseases (such as stroke) in China for many years. The pharmacological properties of DHI include anti-inflammatory, anti-oxidant, anti-coagulatory, hypolipidemic, anti-apoptotic, vasodilatory, and angiogenesis-promoting actions. DHI offers a safe and effective therapeutic agent against cardiovascular and cerebrovascular diseases by modulating multiple disease-relevant signaling pathways and molecular targets. Herein, we provide a comprehensive review of the phytochemistry, therapeutic effects, molecular mechanisms, and adverse reactions of DHI in cardiovascular and cerebrovascular diseases. We also highlight the latest pharmacological advances and therapeutic potential of this promising herb-derived cardiovascular drug preparation.

Proteoglycans Synthesized by Arterial Smooth Muscle Cells in the Presence of Transforming Growth Factor-β1 Exhibit Increased Binding to LDLs

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 2002

DOI: 10.1161/HQ0102.101100

Abstract: The “response-to-retention” hypothesis of atherogenesis states that atherogenic lipoproteins, such as low density lipoprotein (LDL), are retained in vessels by proteoglycans and undergo proatherosclerotic modifications. Transforming growth factor (TGF)-β1 has been identified in atherosclerotic vessels and has been shown to stimulate the synthesis of chondroitin sulfate– and dermatan sulfate–containing proteoglycans by arterial smooth muscle cells (ASMCs), but whether it promotes lipid retention has not been addressed. We investigated whether TGF-β1 modulates the biosynthesis of proteoglycans by ASMCs in a manner that promotes binding to LDL. Proteoglycans isolated from TGF-β1–treated ASMCs exhibited enhanced binding to native LDL compared with the binding of proteoglycans isolated from control cultures ( K d 18 μg/mL LDL versus 81 μg/mL LDL, respectively). The increase in proteoglycan-LDL binding caused by TGF-β1 could be attributed primarily to the glycosaminoglycan portion of the proteoglycans, since the glycosaminoglycan chains liberated from the core proteins of these proteoglycans synthesized in the presence of TGF-β1 exhibited increased LDL binding as well. Furthermore, glycosaminoglycan chains initiated on xyloside (an initiator of glycosaminoglycan synthesis) in the presence of TGF-β1 were longer and displayed enhanced binding to LDL compared with the LDL binding of xyloside-initiated glycosaminoglycan chains from control cultures. These results indicate that TGF-β1 promotes LDL-proteoglycan interaction primarily by its effects on the glycosaminoglycan synthetic machinery of the ASMCs. Therefore, this study supports a proatherogenic role for TGF-β1.

Lithium ions attenuate serum-deprivation-induced apoptosis in PC12 cells through regulation of the Akt/FoxO1 signaling pathways

Publisher: Springer Science and Business Media LLC

Date: 02-12-2015

DOI: 10.1007/S00213-015-4168-7

Abstract: Lithium is currently used in the treatment of mental illness. We have previously reported that lithium stimulated the protein kinase B/Forkhead box O1 (Akt/FoxO1) pathway in rats. However, little information is available regarding its neuroprotective role of this pathway and underlying mechanisms. PC12 cells treated with serum deprivation were used as a toxicity model to study the protective effect of lithium and its underlying mechanisms. Cell viability was determined by methyl thiazolyl tetrazolium assay and Hoechst staining. FoxO1 subcellular location and its overexpression were used to study the underlying mechanisms. Various pathway inhibitors were used to investigate the possible pathways, while the phosphorylation of Akt and FoxO1 was analyzed by Western blot. Lithium pretreatment dose-dependently reduced PC12 cell apoptosis induced by serum starvation. The protective effect of lithium was abolished by LY294002, a PI3K-specific inhibitor, and Akt inhibitor Akt inhibitor VIII, whereas mitogen-activated protein kinase kinase (MEK kinase) inhibitor U0126 had no effect. Lithium induced the phosphorylation of Akt and FoxO1 in a time- and concentration-dependent manner. Lithium-induced phosphorylation of Akt and FoxO1 is mediated by the PI3K/Akt pathway. Serum deprivation caused nuclear translocation of FoxO1 while application of lithium reversed the effect of serum deprivation. Moreover, overexpression of FoxO1 enhanced cell apoptosis induced by serum withdrawal. Finally, lithium was found to reduce the exogenous and endogenous FoxO1 protein levels in PC12 cells in a concentration-dependent fashion. The protective effect of lithium against serum starvation cell death is mediated by the PI3K/Akt/FoxO1 pathway.

Glutamate Attenuates the Survival Property of IGFR through NR2B Containing N-Methyl-D-aspartate Receptors in Cortical Neurons

Publisher: Hindawi Limited

Date: 12-08-2020

DOI: 10.1155/2020/5173184

Abstract: Glutamate-induced neurotoxicity is involved in various neuronal diseases, such as Alzheimer’s disease. We have previously reported that glutamate attenuated the survival signaling of insulin-like growth factor-1 (IGF-1) by N-methyl-D-aspartate receptors (NMDARs) in cultured cortical neurons, which is viewed as a novel mechanism of glutamate-induced neurotoxicity. However, the phosphorylation sites of IGF-1 receptor (IGF-1R) affected by glutamate remain to be elucidated, and importantly, which subtype of NMDARs plays a major role in attenuating the prosurvival effect of IGF-1 is still unknown. In the present study, glutamate was found to attenuate the tyrosine phosphorylation of the IGF-1R and the prosurvival effect of IGF-1 in primary cultured cortical neurons. NMDAR inhibitors, MK801 and AP-5, blocked the inhibitory effect of glutamate on the phosphorylation of IGF-1R and increased cell survival, while DNQX, LY341495, and CPCCOEt had no effect. Interestingly, we found that glutamate decreased the phosphorylation of tyrosine residues 1131, 1135/1136, 1250/1251, and 1316, while it had no effect on tyrosine 950 in cortical neurons. Moreover, using specific antagonists and siRNA to downregulate in idual NMDAR subunits, we found that the activation of NR2B-containing NMDARs was essential for glutamate to inhibit IGF-1 signaling. These findings indicate that the glutamate-induced attenuation of IGF-1 signaling is mediated by NR2B-containing NMDARs. Our study also proposes a novel mechanism of altering neurotrophic factor signaling by the activation of NMDARs.

Tanshinone II-A inhibits oxidized LDL-induced LOX-1 expression in macrophages by reducing intracellular superoxide radical generation and NF-κB activation

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1016/J.TRSL.2012.01.008

Abstract: Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1), a novel scavenger receptor highly expressed in human and experimental atherosclerotic lesions, is responsible for the uptake of oxLDL in vascular cells. We demonstrated previously that Tanshinone II-A (Tan), a pharmacologically active compound extracted from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge, inhibits atherogenesis in hypercholesterolemic rats, rabbits, and apolipoprotein-E deficient (ApoE⁻/⁻) mice. However, the precise mechanism by which Tan protects against atherogenesis remains to be elucidated. Therefore, we hypothesized that Tan can suppress the uptake of oxLDL by diminishing the expression of LOX-1 via suppression of NF-κB signaling pathway, thereby contributing to reduced macrophage foam cell formation. In cultured murine macrophages, oxLDL induced LOX-1 expression at the mRNA and protein levels, was abrogated by addition of Tan or pyrrolidinedithiocarbamic acid ammonium salt (PDTC), a widely used inhibitor of NF-κB, suggesting the involvement of NF-κB. Tan also reduced LOX-1 expression in atherosclerotic lesions of ApoE⁻/⁻ mice fed a high cholesterol diet. Mechanistically, Tan suppressed the nuclear translocation of NF-κB P65 subunit and phosphorylation of IκB-α induced by oxLDL. Electrophoretic mobility shift assay (EMSA) demonstrated that Tan inhibited the nuclear protein binding to NF-κB consensus sequence. Functionally, we observed that Tan inhibited DiI-oxLDL uptake by macrophages in a fashion similar to that produced by LOX-1 neutralizing antibody. Our current findings reveal a novel mechanism by which Tan protects against atherogenesis and shed new light on the potential therapeutic application of Tan to the treatment and prevention of atherosclerotic cardiovascular diseases.

Glimpses of the mechanisms of hypertension.

Publisher: BMJ

Date: 29-11-1986

DOI: 10.1136/BMJ.293.6559.1436-C

Abstract: In the crystal structure of the title compound, C(13)H(9)ClO(3), the mol-ecules form classical O-H⋯O hydrogen-bonded carb-oxy-lic acid dimers. These dimers are linked by C-H⋯π inter-actions into a three-dimensional network. The benzene rings are oriented at a dihedral angle of 77.8 (1)°.

Glycosaminoglycan synthesis and structure as targets for the prevention of calcific aortic valve disease

Publisher: Oxford University Press (OUP)

Date: 10-2007

DOI: 10.1016/J.CARDIORES.2007.05.014

Abstract: Calcific aortic valve disease is frequently driven by ageing and the obesity-associated metabolic syndrome, and the increasing impact of these factors indicates that valve disease will become a cardiovascular disease of considerable significance. This disease is now thought to be an active cell-based disease process, which may therefore be amenable to therapeutic intervention. Some similarities are apparent with atherosclerosis. The accumulation of lipid, possibly by retention by proteoglycans and the attraction of inflammatory cells by hyaluronan, may be common to the early stages of both pathologies. The synthesis and structure of glycosaminoglycans, proteoglycans, and hyaluronan are exquisitely regulated, and the signalling pathways controlling these processes may provide tissue-specific opportunities for concomitant prevention of atherosclerosis and calcific aortic valve disease.

The zinc finger transcription factor, KLF2, protects against COVID-19 associated endothelial dysfunction

Publisher: Springer Science and Business Media LLC

Date: 12-07-2021

DOI: 10.1038/S41392-021-00690-5

Abstract: Coronavirus disease 2019 (COVID-19) is regarded as an endothelial disease (endothelialitis) with its patho-mechanism being incompletely understood. Emerging evidence has demonstrated that endothelial dysfunction precipitates COVID-19 and its accompanying multi-organ injuries. Thus, pharmacotherapies targeting endothelial dysfunction have potential to ameliorate COVID-19 and its cardiovascular complications. The objective of the present study is to evaluate whether kruppel-like factor 2 (KLF2), a master regulator of vascular homeostasis, represents a therapeutic target for COVID-19-induced endothelial dysfunction. Here, we demonstrate that the expression of KLF2 was reduced and monocyte adhesion was increased in endothelial cells treated with COVID-19 patient serum due to elevated levels of pro-adhesive molecules, ICAM1 and VCAM1. IL-1β and TNF-α, two cytokines elevated in cytokine release syndrome in COVID-19 patients, decreased KLF2 gene expression. Pharmacologic (atorvastatin and tannic acid) and genetic (adenoviral overexpression) approaches to augment KLF2 levels attenuated COVID-19-serum-induced increase in endothelial inflammation and monocyte adhesion. Next-generation RNA-sequencing data showed that atorvastatin treatment leads to a cardiovascular protective transcriptome associated with improved endothelial function (vasodilation, anti-inflammation, antioxidant status, anti-thrombosis/-coagulation, anti-fibrosis, and reduced angiogenesis). Finally, knockdown of KLF2 partially reversed the ameliorative effect of atorvastatin on COVID-19-serum-induced endothelial inflammation and monocyte adhesion. Collectively, the present study implicates loss of KLF2 as an important molecular event in the development of COVID-19-induced vascular disease and suggests that efforts to augment KLF2 levels may be therapeutically beneficial.

Elucidating the role of the FoxO3a transcription factor in the IGF-1-induced migration and invasion of uveal melanoma cancer cells

Publisher: Elsevier BV

Date: 12-2016

DOI: 10.1016/J.BIOPHA.2016.11.027

Abstract: Uveal melanoma (UM) is the most common primary intraocular malignant tumor of adults. It has high mortality rate due to liver metastasis. However, the epidemiology and pathogenesis of liver metastasis in UM are not elucidated and there is no effective therapy available for preventing the development of this disease. IGF-1 is a growth factor involved in cell proliferation, malignant transformation and inhibition of apoptosis. In previous report, IGF-1 receptor was found to be highly expressed in UM and this was related to tumor prognosis. FoxO3a is a Forkhead box O (FOXO) transcription factor and a downstream target of the IGF-1R/PI3K/Akt pathway involved in a number of physiological and pathological processes including cancer. However, the role of FoxO3a in UM is unknown. In the present study, we investigated fundamental mechanisms in the growth, migration and invasion of UM and the involvement of FoxO3a. IGF-1 increased the cell viability, invasion, migration and S-G2/M cell cycle phase accumulation of UM cells. Western blot analysis showed that IGF-1 led to activation of Akt and concomitant phosphorylation of FoxO3a. FoxO3a phosphorylation was associated with its translocation into the cytoplasm from the nucleus and its functional inhibition led to the inhibition of expression of Bim and p27, but an increase in the expression of Cyclin D1. The effects of IGF-1 on UM cells were reversed by LY294002 (a PI3K inhibitor) or Akt siRNA, and the overexpression of FoxO3a also attenuated basal invasion and migration of UM. Taken all together, these results suggest that inhibition of FoxO3a by IGF-1 via the PI3K/Akt pathway has an important role in IGF-1 induced proliferation and invasion of UM cells. These findings also support FoxO3a and IGF signaling may represent a valid target for investigating the development of new strategies for the treatment and prevention of the pathology of UM.

Thiazolidinedlones reduce the LDL binding affinity of non-human primate vascular cell proteoglycans

Publisher: Springer Science and Business Media LLC

Date: 05-2004

DOI: 10.1007/S00125-004-1358-Y

Abstract: Retention of atherogenic lipoproteins in the artery wall by proteoglycans is a key step in the development of atherosclerosis. Thiazolidinediones have been shown to reduce atherosclerosis in mouse models. The aim of this study was to determine whether thiazolidinediones modify vascular proteoglycan synthesis in a way that decreases LDL binding. Primate aortic smooth muscle cells were exposed to troglitazone or rosiglitazone, or no stimulus at all for a 24-hour steady-state labelling period. Sulphate incorporation, size and LDL binding affinity of proteoglycans were determined. Proteoglycans secreted by cells in the presence or absence of troglitazone were separated into large and small classes by size exclusion chromatography, and LDL binding affinity was determined. Proteoglycans synthesised by cells exposed to troglitazone or rosiglitazone were smaller, with decreased sulphate incorporation and decreased LDL binding affinity. However, troglitazone had a greater effect than rosiglitazone. Troglitazone reduced the LDL binding affinities of both the large and small proteoglycans compared with control. The binding differences persisted when glycosaminoglycan chains released from proteoglycans were incubated with LDL, indicating that troglitazone affects the glycosaminoglycan synthetic machinery of these cells. Thiazolidinediones decrease the LDL binding affinity of the proteoglycans synthesised by primate aortic smooth muscle cells. This could, in part, account for the reduced atherosclerosis observed in animal models.

G protein coupled receptors can transduce signals through carboxy terminal and linker region phosphorylation of Smad transcription factors

Publisher: Elsevier BV

Date: 04-2018

DOI: 10.1016/J.LFS.2018.03.004

Abstract: Smads (sma/mothers against decapentaplegic) are transcription factors, which can be phosphorylated in the carboxy terminal (pSmad2/3C) or in the structurally central linker region (pSmad2/3 L). Only receptor kinases such as Transforming Growth Factor (TGF)-β receptor (TGFBR1) can mediate carboxy terminal phosphorylation but multiple receptors, including TGFBR1 itself, can activate cytosolic serine/threonine kinases and mediate serine/threonine (S/T) linker region phosphorylation of Smad2/3. One important class of agents that can mediate Smad phosphorylation are the G protein coupled receptors (GPCRs) and their ligands and these agents can meditate both carboxy terminal and linker region phosphorylation. Linker region phosphorylation arises due to activation of kinases including those downstream of the transactivation of the EGFR and carboxy terminal Smad phosphorylation can occur as a result of the recently described activity of GPCRs, notably protease activated receptors (PAR)-1, to transactivate TGFBR1 leading to direct carboxy terminal Smad phosphorylation. This review will summarize the effects of GPCR-mediated receptor transactivation pathways on the phosphorylation of Smad2 linker region, as a better understanding of these pathways may provide new approaches for the identification of novel therapeutic agents.

Role of brain-derived neurotrophic factor and nerve growth factor in the regulation of Neuropeptide W in vitro and in vivo

Publisher: Elsevier BV

Date: 05-2017

DOI: 10.1016/J.MCE.2017.02.040

Abstract: Nerve growth factor (NGF) and Brain-derived neurotrophic factor (BDNF) are neurotrophic factors involved in the growth, survival and functioning of neurons. In addition, a possible role of neurotrophins, particularly BDNF, in HPA axis hyperactivation has recently been proposed. Neuropeptide W (NPW) is an endogenous peptide ligand for the GPR7 and GPR8 and a stress mediator in the hypothalamus. It activates the HPA axis by working on hypothalamic corticotrophin-releasing hormone (CRH). No information is available about the interrelationships between neurotrophines like NGF/BDNF and NPW. We studied the effect and underlying mechanisms of NGF/BDNF on the production of NPW in PC12 cells and hypothalamus. NGF time- and concentration-dependently stimulated the expression of NPW in PC12 cells. The effect of NGF was blocked by the inhibition of PI3K/Akt signal pathway with specific inhibitors for PI3K or AktsiRNA for Akt while inhibition of ERK pathway had no effect. Moreover, BDNF concentration-dependently induced the expression of NPW mRNA and decreased the expression of NPY mRNA in primary cultured hypothalamic neurons which was also blocked by a PI3K kinase inhibitor. Finally, in vivo study showed that exogenous BDNF injected icv increased NPW production in the hypothalamus and this effect was reversed by a PI3 kinase inhibitor. These results and the fact that BDNF was able to stimulate the expression of CRH demonstrated that neurotrophines can modulate the expression of NPW in neuronal cells via the PI3K/Akt pathway and suggest that BDNF might be involved in functions of the HPA axis, at least in part by modulating the expression of NPW/NPY and CRH.

Inositol phosphate release and steroidogenesis in rat adrenal glomerulosa cells. Comparison of the effects of endothelin, angiotensin II and vasopressin

Publisher: Portland Press Ltd.

Date: 11-1990

DOI: 10.1042/BJ2710791

Abstract: Endothelin has steroidogenic activity in adrenal glomerulosa cells, as do two other vasoconstrictor peptides, angiotensin II and vasopressin. The steroidogenic activities of angiotensin II and vasopressin are probably mediated via the phosphatidylinositol-turnover pathway and associated changes in cytosolic Ca2+ concentration. Endothelin caused a steroidogenic response, which was small compared with that to angiotensin II and quantitatively similar to the vasopressin response. Cytosolic free Ca2+ responses were similarly higher to angiotensin II than to either of the other two peptides. However, total inositol phosphate responses to endothelin and angiotensin II were similar when these were measured over 20 min, and were quantitatively greater than the vasopressin response. A detailed study has been made of the phosphatidylinositol-turnover response to endothelin in comparison with responses to angiotensin II and vasopressin. Each of the three peptides produced a rapid and transient rise in Ins(1,4,5)P3 (max. 5-15 s), followed by a slow sustained rise. Ins(1,4,5)P3 was metabolized by both dephosphorylation and phosphorylation pathways, but the relative importance of the two metabolic pathways was different under stimulation by each of the three peptides. These findings show that adrenal glomerulosa cells can distinguish between the stimulation of phosphatidylinositol turnover by three different effectors. These differences in the pathway may be associated with the observed different steroidogenic and Ca2+ responses to the three peptides.

Thrombin regulates vascular smooth muscle cell proteoglycan synthesis via PAR-1 and multiple downstream signalling pathways

Publisher: Elsevier BV

Date: 12-2008

DOI: 10.1016/J.THROMRES.2008.04.019

Abstract: Atherosclerosis is the underlying pathological process of most cardiovascular disease. Thrombin is a serine protease which can activate protease activated receptors (PAR) on vascular smooth muscle cells (VSMC) to elicit cellular responses that can contribute to the pathogenesis of atherosclerosis. Human atherosclerosis commences with the binding and retention of lipoproteins by the glycosaminoglycan (GAG) chains of chondroitin/dermatan sulfate proteoglycans. The potential effects of thrombin on the synthesis and structure of CS/DS proteoglycans produced by VSMCs was investigated. VSMCs were derived from human internal mammary arteries. Proteoglycan synthesis was assessed by [(35)S]sulfate and [(3)H]glucosamine incorporation. Proteoglycan size was assessed by SDS-PAGE and size exclusion chromatography. Thrombin caused a dose-dependent increase in [(35)S]sulfate and [(3)H]glucosamine incorporation with maximum effects of approximately 150% at the highest doses tested. This increase was associated with increased size of biglycan and decorin assessed by SDS-PAGE. Chemically cleaved glycosaminoglycan (GAG) chains analyzed by SDS-PAGE and size exclusion chromatography were larger for proteoglycans from thrombin treated cells. VSMCs synthesize small GAGs when provided with exogenous xyloside and thrombin treatment also increased the size of the secreted xyloside GAGs. The effect of thrombin was not mimicked by the catalytically inactive FPRCK-HCT and was blocked in a concentration- dependent manner by the PAR-1 antagonist, JNJ5177049. Inhibition of PK C with GF 109203X resulted in concentration dependent but partial inhibition of [(35)S]sulfate incorporation accompanied by a reduction in the size of biglycan and decorin. Epidermal growth factor (EGF) stimulated [(35)S]sulfate incorporation and increased proteoglycan size and this was completely blocked by the EGF receptor tyrosine kinase inhibitor AG1478. AG1478 partially (32%, p<0.01) blocked the effect of thrombin. Thrombin treatment of VSMCs increased the proportion of disaccharides sulfated at the 6 position of the GalNAc residues. Thus, thrombin has actions on VSMCs which increase the length and modify the sulfation pattern of GAG chains on proteoglycans in a manner that would enhance the binding of LDL. If manifest in vivo, this effect on proteoglycan synthesis and structure represents a new biochemical mechanism through which thrombin contributes to the development of atherosclerosis.

New Approaches to Regulating the Chondroitin/Dermatan Sulfate Glycosaminoglycan Component of the Vascular Extracellular Matrix

Publisher: Hindawi Limited

Date: 2201

DOI: 10.1100/TSW.2005.69

Flavopiridol Inhibits TGF-β-Stimulated Biglycan Synthesis by Blocking Linker Region Phosphorylation and Nuclear Translocation of Smad2

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 09-02-2018

DOI: 10.1124/JPET.117.244483

Abstract: Transforming growth factor-

Thrombin promotes PAI-1 expression and migration in keratinocytes via ERK dependent Smad linker region phosphorylation

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.CELLSIG.2018.03.009

Abstract: Keratinocyte proliferation and migration is essential during re-epithelialisation for the restoration of the epithelial barrier during skin wound healing. Numerous growth factors are involved in the stimulation of keratinocyte proliferation and migration. The signalling pathways that drive these processes during wound healing are not well defined. This study investigated thrombin-mediated signalling in keratinocytes. The thrombin receptor, protease-activated receptor 1 (PAR-1) is a seven transmembrane G-protein coupled receptor that is known to transactivate the epidermal growth factor receptor (EGFR). Immortalized human keratinocytes (HaCaT cells) were treated with thrombin and selective inhibitors to EGFR and MAP kinases. Whole cell lysates were separated on SDS-PAGE and analysed by Western blot using antibodies against transcription factor Smad2. Quantitative real-time polymerase chain reaction was used to measure the mRNA expression of PAI-1 while scratch wound assays were used to measure keratinocyte migration. Western blot data showed that thrombin mediates PAR-1 transactivation of EGFR and the downstream phosphorylation of the transcription factor Smad2 linker (Smad2L) region. ERK1/2 inhibition by UO126 caused a decrease in Smad2L phosphorylation while the p38 inhibitor SB202190 and JNK inhibitor SP600125 did not. Smad2L Ser250 was specifically phosphorylated by this thrombin mediated pathway while Ser245 and Ser255 were not. Thrombin increased PAI-1 mRNA expression and keratinocyte migration and this was reduced when either EGFR or ERK1/2 were blocked. Taken together these results show that thrombin mediated mRNA expression of PAI-1 in keratinocytes and migration occurs via EGFR transactivation and involves signalling intermediates ERK1/2 and Smad2 and may be a key pathway in skin wound healing.

Potential of Small Molecule Protein Tyrosine Kinase Inhibitors as Immunomodulators and Inhibitors of the Development of Diabetes

Publisher: Hindawi Limited

Date: 2009

DOI: 10.1100/TSW.2009.28

Anti-proliferative activity of oral anti-hyperglycemic agents on human vascular smooth muscle cells: thiazolidinediones (glitazones) have enhanced activity under high glucose conditions

Publisher: Springer Science and Business Media LLC

Date: 2007

DOI: 10.1186/1475-2840-6-33

G protein coupled receptor transactivation: Extending the paradigm to include serine/threonine kinase receptors

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.BIOCEL.2012.01.018

Abstract: The current paradigm of G protein coupled receptor signaling involves a classical pathway being the activation of phospholipase C and the generation of 1,4,5-inositol trisphosphate, signaling through β-arrestin scaffold molecules and the transactivation of tyrosine kinase growth factor receptors. Transactivation greatly expands the range of signaling pathways and responses attributable to the receptor. Recently it has been revealed that G protein coupled receptor agonists can also transactivate the serine/threonine kinase cell surface receptor for transforming growth factor-β (Alk5). This leads to the generation of carboxyl terminal phosphorylated Smad2 which is the immediate downstream product of the activated Alk5. Thus, the current paradigm of G protein coupled signaling can be expanded to include the transactivation of the serine kinase receptor Alk5. These insights expand the possibilities for outcomes of therapeutically targeting GPCRs where more substantive and prolonged actions such as the synthesis of extracellular matrix may be affected.

Phosphorylated Troglitazone Activates PPARγ and Inhibits Vascular Smooth Muscle Cell Proliferation and Proteoglycan Synthesis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2008

DOI: 10.1097/FJC.0B013E3181626CE7

TWO PATIENTS WITH ABNORMALITIES OF REGIONAL SYMPATHETIC NERVOUS TONE

Publisher: Wiley

Date: 12-1984

DOI: 10.1111/J.1445-5994.1984.TB03789.X

Abstract: The traditional biochemical tests of sympathetic nervous system function used in clinical diagnosis (urine and plasma catecholamine measurements) are indices of "overall" sympathetic nervous activity, and incapable of detecting localised changes in sympathetic tone confined to in idual organs. Recently developed radiotracer methods, which enable the pattern of sympathetic nervous dysfunction in disease states to be delineated, were used to detect abnormalities in regional sympathetic nervous system activity in two patients presenting problems in management. In one, the abnormality of sympathetic function was iatrogenic, a post-sympathectomy denervation of the lower regions of the body, associated with incapacitating postural hypotension. In the other, unexplained persistent sinus tachycardia proved to be due to an increase in sympathetic nervous tone restricted to the innervation of the heart. Knowledge of the underlying sympathetic nervous pathophysiology in these patients influenced the choice of drugs subsequently used in their treatment.

MECHANISMS INVOLVED IN THE STIMULATION OF ALDOSTERONE PRODUCTION BY ANGIOTENSIN II, VASOPRESSIN AND ENDOTHELIN

Publisher: Wiley

Date: 04-1990

DOI: 10.1111/J.1440-1681.1990.TB01318.X

Abstract: 1. Endothelin (ET), vasopressin (VP) and angiotensin II (AII) all stimulate aldosterone production in adrenal glomerulosa cells but the response to AII is greater than that to either ET or VP. 2. Total inositol phosphate responses to AII and ET were similar but the response to VP was lower. 3. Cytosolic free Ca2+ responses to AII were higher than to either of the other peptides. 4. Metabolism of 145IP3 was different under stimulation by the three different peptides. 5. Adrenal glomerulosa cells can distinguish between three different agonists which stimulate phosphatidylinositol turnover and produce a selective response to each peptide.

The pH of spontaneously beating cultured rat heart cells is regulated by an ATP-calmodulin-dependent Na+/H+ antiport.

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 04-1989

DOI: 10.1161/01.RES.64.4.676

Abstract: We investigated the mechanisms by which spontaneously beating cultured rat ventricular cells regulate intracellular pH (pHi). Specifically, the relative contributions of the Na+/H+ antiport, Cl-/HCO3- exchange, ATP, and calmodulin-dependent processes in regulating the pHi of cells loaded with the intracellular fluorescent pH indicator BCECF were investigated. The pHi of ventricular cells bathed in HEPES-buffered medium averaged 7.30 +/- 0.02. Subsequent exposure of the cells to CO2-HCO3- -buffered medium resulted in intracellular acidification followed by recovery to pHi levels approximately 0.1 pH units lower than in controls. Recovery was inhibited by the Na+/H+ antiport inhibitor 5-(N-ethyl-N-isopropyl)amiloride (EIPA). The recovery from intracellular acidification, induced by a 15-mM ammonium chloride prepulse, was also dependent solely upon activation of the Na+/H+ antiport. Recovery was dependent upon extracellular sodium, was completely inhibited by EIPA, and could be modulated by changes in extracellular pH (pHo). At low pHo values (6.3) the recovery of pHi was greatly attenuated, while at high pHo (8.0) the recovery process was accelerated. The final pHi to which the cells recovered was also dependent upon pHo. Preincubation of the cells with 2-deoxy-D-glucose to deplete cellular ATP levels reduced pHi by approximately 0.2 pH units and greatly impaired the cells' ability to recover from 15-mM ammonium chloride-induced acid load. Similarly, preincubation of cells with the calmodulin inhibitors W-7 and trifluoperazine also impaired their ability to recover from the acid load. The Cl- -HCO3- exchange played no role in the cells' ability to recover from intracellular acidosis. However, the presence of HCO3- significantly increased the resistance of myocardial cells to changes in pHi by approximately doubling their buffer capacity. These results demonstrated that a Na+/H+ antiport is the major pHi-regulating system in spontaneously beating rat ventricular cells. The ability of the Na+/H+ antiport to regulate myocardial pHi is dependent upon the cells' ability to maintain adequate levels of ATP. The antiport's dependency on ATP, in conjunction with its dependency on calmodulin, suggests that activation of the antiport in ventricular cells involves phosphorylation processes.

Characterization of intracellular translocation of Forkhead transcription factor O (FoxO) members induced by NGF in PC12 cells

Publisher: Elsevier BV

Date: 07-2011

DOI: 10.1016/J.NEULET.2011.04.055

Abstract: Nuclear translocation of Forkhead transcription factors of the O class (FoxOs) is important for the action of growth factors. However it is not known if all members of the FOXO family have the same translocation properties. We examined the effects of nerve growth factor (NGF) on nuclear/cytoplasmic shuttling of FoxO1, FoxO3a and FoxO6 in PC12 cells and determined their translocation kinetics. Our data demonstrated that NGF could induce the nuclear exclusion of FoxO1-GFP and FoxO3a-GFP in PC12 cells with different properties, but had no effect on FoxO6-GFP's nuclear localization and FoxO6-GFP showed an exclusive nuclear localization. Translocat ould be blocked by K252a and LY294002 but not by PD98059. Moreover, FoxO3a returned to cytoplasm at a higher rate than FoxO1 after NGF stimulation and it was more sensitive than FoxO1 to NGF stimulation.

Protease activated receptor-1 mediated dual kinase receptor transactivation stimulates the expression of glycosaminoglycan synthesizing genes

Publisher: Elsevier BV

Date: 2016

DOI: 10.1016/J.CELLSIG.2015.11.003

Abstract: G protein-coupled receptors (GPCR) are one of the most important targets for therapeutics due to their abundance and ersity. The G protein-coupled receptor for thrombin can transactivate protein tyrosine kinase receptors (PTKR) and we have recently established that it can also transactivate serine/threonine kinase receptors (S/TKR). A comprehensive knowledge of the signalling pathways that GPCR transactivation elicits is necessary to fully understand the implications of both GPCR activation and the impact of target drugs. Here, we demonstrate that thrombin elicits dual transactivation-dependent signalling pathways to stimulate mRNA expression of glycosaminoglycan synthesizing enzymes chondroitin 4-O-sulfotransferase 1 and chondroitin sulfate synthase 1. The PTKR mediated response involves matrix metalloproteinases and the phosphorylation of the MAP kinase Erk. The S/TKR mediated response differs markedly and involves the phosphorylation of Smad2 carboxy terminal serine residues and does not involve matrix metalloproteinases. This work shows that all of the thrombin mediated signalling to glycosaminoglycan synthesizing enzyme gene expression occurs via transactivation-dependent pathways and does not involve transactivation-independent signalling. These findings highlight the complexity of thrombin-mediated transactivation signalling and the broader implications of GPCR targeted therapeutics.

IGF-1-Mediated Survival from Induced Death of Human Primary Cultured Retinal Pigment Epithelial Cells Is Mediated by an Akt-Dependent Signaling Pathway

Publisher: Springer Science and Business Media LLC

Date: 25-02-2017

DOI: 10.1007/S12035-017-0447-0

Abstract: Degeneration of the human retinal pigmented epithelium (hRPE) is involved in several eye disorders such as age-related macular degeneration (AMD). In this study, we investigated the protective effect of IGF-1 on human primary cultured RPE cells and its underlying mechanism. IGF-1 dose- and time-dependently promoted the survival of RPE cells from serum deprivation. Western blot showed that IGF-1 stimulated the activation of the PI3K/Akt and MAPK pathways in hRPE. Inhibition of the PI3K/Akt pathway by the PI3K-specific inhibitor, LY294002 or inhibition of Akt by Akt-specific inhibitors Akt inhibitor VIII or SN-38, or downregulation Akt with siRNA specific for Akt blocked the effect of IGF-1 on hRPE. In contrast, blockade of the MAPK pathway with a specific inhibitor PD98059 had no effect. Interestingly, vitreous IGF-1 injection reversed the inhibitory effect of light exposure (a dry AMD model) on both a wave and b wave. Immunocytochemistry showed that vitreous IGF-1 injections promoted the survival of RPE cells in rat retina and the expression of RPE65 in RPE cells from light injury. These results indicate that IGF-1 is able to protect hRPE cell from different insults in vivo and in vitro. Further detailed studies may lead the way to a therapeutic intervention for retinal diseases in which cell death is an underlying contributory mechanism.

The Nerve Growth Factor Signaling and Its Potential as Therapeutic Target for Glaucoma

Publisher: Hindawi Limited

Date: 2014

DOI: 10.1155/2014/759473

Abstract: Neuroprotective therapies which focus on factors leading to retinal ganglion cells (RGCs) degeneration have been drawing more and more attention. The beneficial effects of nerve growth factor (NGF) on the glaucoma have been recently suggested, but its effects on eye tissue are complex and controversial in various studies. Recent clinical trials of systemically and topically administrated NGF demonstrate that NGF is effective in treating several ocular diseases, including glaucoma. NGF has two receptors named high affinity NGF tyrosine kinase receptor TrkA and low affinity receptor p75NTR. Both receptors exist in cells in retina like RGC (expressing TrkA) and glia cells (expressing p75NTR). NGF functions by binding to TrkA or p75NTR alone or both together. The binding of NGF to TrkA alone in RGC promotes RGC’s survival and proliferation through activation of TrkA and several prosurvival pathways. In contrast, the binding of NGF to p75NTR leads to apoptosis although it also promotes survival in some cases. Binding of NGF to both TrkA and p75NTR at the same time leads to survival in which p75NTR functions as a TrkA helping receptor. This review discusses the current understanding of the NGF signaling in retina and the therapeutic implications in the treatment of glaucoma.

Leu143 in the Putative Fourth Membrane Spanning Domain Is Critical for Amiloride Inhibition of an Epithelial Na+/H+ Exchanger Isoform (NHE-2)

Publisher: Elsevier BV

Date: 06-1993

DOI: 10.1006/BBRC.1993.1656

Abstract: A family of Na+/H+ exchanger isoforms (called NHE1, NHE2, and NHE3) which exhibits a wide range of amiloride sensitivity has recently been cloned and characterized. A part of the domain, which determines amiloride sensitivity in the epithelial Na+/H+ exchanger isoform, NHE2, was identified by site-directed mutagenesis and functional studies using cDNAs stably expressed in a fibroblast cell line. It has previously been reported that AR300, an amiloride resistant mutant of the ubiquitous Na+/H+ exchanger isoform, NHE1, is 30-fold more resistant to methylpropyl amiloride (MPA) compared to NHE1 and contains a single amino acid substitution of L167F in the fourth putative transmembrane helix, which corresponds to L143 in NHE2. Therefore, in the present study point mutational substitutions were introduced into the equivalent of this fourth transmembrane helix of rabbit NHE2 (including Y144F L143F L143F and Y144F) to mimic the corresponding amino acids in NHE1, NHE3 (another epithelial isoform) and AR300, respectively. NHE2/L143F (mimicking NHE3) increased the IC50 for amiloride by 5-fold and for ethylisopropyl amiloride (EIPA) by 20-fold. Similarly, NHE2/L143F and Y144F (mimicking AR300) increased the resistance to both amiloride and EIPA by 10-fold. On the other hand, NHE2/Y144F (mimicking NHE1) did not affect the sensitivity to amiloride or EIPA, and this mutant, like wild type NHE2, is partially resistant to EIPA. Thus, amino acid 143 of NHE2 is critical for, but is not the only amino acid responsible for, amiloride and EIPA inhibition of Na+/H+ exchange. That none of the mutations studied altered the Na+ affinity of these Na+/H+ exchangers further suggests that amiloride binding and Na+ transport sites are not identical.

Individual Smad2 linker region phosphorylation sites determine the expression of proteoglycan and glycosaminoglycan synthesizing genes

Publisher: Elsevier BV

Date: 2019

DOI: 10.1016/J.CELLSIG.2018.11.005

Forkhead box O transcription factors as possible mediators in the development of major depression

Publisher: Elsevier BV

Date: 12-2015

DOI: 10.1016/J.NEUROPHARM.2015.08.020

Abstract: Forkhead box O (FoxO) transcription factors play important roles in cellular physiology and biology. Recent findings indicate that FoxOs are also involved in the development of major depressive disorder. Alterations in the upstream molecules of FoxOs, such as brain derived neurotrophic factor or protein kinase B, have been linked to depression. Antidepressants, such as imipramine and venlafaxine, modify the FoxOs phosphorylation. Furthermore, FoxOs could be regulated by serotonin and norepinephrine receptor signaling as well as the hypothalamic-pituitary-adrenal axis, all of which are involved in the pathogenesis of depression. FoxOs also regulate neuronal morphology, synaptogenesis and adult hippoc al neurogenesis, which are viewed as candidate mechanisms for the etiology of depression. In this review, we emphasize the possible roles of FoxOs during the development of depression and make some strategic recommendations for future research. We propose that FoxOs and its signaling pathways may constitute potential therapeutic targets in the treatment of depression.

FOXO Signaling Pathways as Therapeutic Targets in Cancer

Publisher: Ivyspring International Publisher

Date: 2017

DOI: 10.7150/IJBS.20052

IONIC MECHANISMS REGULATING SODIUM ENTRY INTO VASCULAR SMOOTH MUSCLE

Publisher: Wiley

Date: 02-1991

DOI: 10.1111/J.1440-1681.1991.TB01419.X

Abstract: 1. Na+/H+ exchange, an ethylisopropylamiloride (EIPA)-sensitive Na+ and HCO3- dependent system and a diisothio-cyanatostilbenedisulphonic acid (DIDS)-sensitive Na+ and HCO3- transporter, contribute to sodium influx and intracellular pH (pHi) regulation in vascular smooth muscle. 2. In cultured cells from the human internal mammary artery, Na+/H+ exchange and the EIPA-sensitive Na+ and HCO3- dependent system contribute about 80% to basal sodium influx. The residual Na+ influx is both EIPA and DIDS-insensitive. 3. Sodium influx via these mechanisms influences the ability of vascular smooth muscle to synthesize protein late in the G1 phase of the mitotic cell cycle. This, in turn, affects DNA biosynthesis. 4. These Na+ exchanges/transporters have the capability to facilitate the development of vascular hypertrophy in hypertension.

The Paradigm of G Protein Receptor Transactivation: A Mechanistic Definition and Novel Example

Publisher: Hindawi Limited

Date: 2011

DOI: 10.1100/TSW.2011.75

Abstract: Seven transmembrane G protein—coupled receptors are among the most common in biology and they transduce cellular signals from a plethora of hormones. As well as their own well-characterized signaling pathways, they can also transactivate tyrosine kinase growth factor receptors to greatly expand their own cellular repertoire of responses. Recent data in vascular smooth muscle cells have expanded the breadth of transactivation to include serine/threonine kinase receptors, specifically the receptor for transforming growth factor beta (TGF-β). Stimulation with endothelin and thrombin leads to the rapid formation of C-terminal phosphorylated Smad2, which is the immediate product of activation of the TGF-β receptor. Additionally, it appears that no definition of transactivation based on mechanism is available, so we have provided a definition involving temporal aspects and the absence of de novo protein synthesis. The phenomenon of transactivation is an important biochemical mechanism and potential drug target in multiple diseases.

Inhibitors of hepatic mixed function oxidases—II Some benzimidazole, benzoxazole and benzothiazole derivatives

Publisher: Elsevier BV

Date: 12-1976

DOI: 10.1016/0006-2952(76)90267-7

p38 MAP Kinase Mediated Proteoglycan Synthesis as a Target for the Prevention of Atherosclerosis

Publisher: Bentham Science Publishers Ltd.

Date: 12-2008

DOI: 10.2174/187152908786786205

Abstract: The major underlying pathology of most cardiovascular disease is the chronic inflammatory disease of atherosclerosis. Type 2 diabetes, also recognised as an inflammatory condition, accelerates the development of atherosclerosis. Current therapies for atherosclerosis target risk factors such as elevated blood lipids and hypertension and are of strong but limited efficacy. The "response to retention" hypothesis states that atherosclerosis is initiated by the accumulation of lipids through binding to extracellular matrix, and this is specifically the glycosaminoglycan (GAG) chains on proteoglycans. Many vasoactive agonists stimulate changes in the structure of the GAGs which increase lipid binding and the relevant signalling pathways are a potential therapeutic target. It has recently been demonstrated that the actions of transforming growth factor beta on vascular smooth muscle proteoglycan synthesis involves signalling through p38 MAP kinase and inhibition of this pathway reduces binding of lipids. Inhibition of p38 MAP kinase will elicit a wide spread anti-inflammatory response which may alleviate some of the deleterious processes in cardiovascular tissues. This article explores the potential for the actions of p38 MAP kinase inhibitors directed at proteoglycan synthesis in vascular smooth muscle to contribute to the beneficial outcomes from targeting p38 MAP kinase for the prevention of cardiovascular disease.

Protection of Neuronal Uptake-1 Inhibitors in Ischemic and Anoxic Hearts by Norepinephrine-Dependent and -Independent Mechanisms

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-1998

DOI: 10.1097/00005344-199810000-00015

Abstract: Cardiac ischemia and anoxia induce massive norepinephrine (NE) release, which is mediated by a reverse operation of uptake-1 and can be suppressed by uptake-1 inhibitors. We studied effects of uptake-1 inhibitors on incidence of ventricular fibrillation (VF%) and myocardial contracture in perfused rat hearts under ischemic or anoxic conditions. NE release occurred in hearts during ischemia or anoxia and was largely inhibited by desipramine, imipramine, and cocaine. The generation of inositol 1,4,5-trisphosphate (InsP3) during reperfusion also was abolished by desipramine. During anoxia/reoxygenation, VF (93 and 71%, respectively) and myocardial contracture occurred and were significantly inhibited by desipramine and by NE depletion. Regional ischemia and reperfusion induced high VF% (86 and 100%, respectively), which was reduced or abolished by desipramine and imipramine at 0.03 and 0.3 microM. During the ischemic phase, cocaine was similarly antiarrhythmic, as was a combination of timolol and prazosin, but NE depletion was not. In NE-depleted hearts, cocaine or the combination of timolol and prazosin showed limited effect on VF%, whereas both desipramine and imipramine abolished VF. In anesthetized rats in vivo, ischemic VF% was reduced by desipramine (30 vs. 92% p < 0.01). In conclusion, uptake-1 inhibitors protect hearts against ischemia/reperfusion- and anoxia/reoxygenation-induced arrhythmias, partly because of the inhibition of locally mediated NE release. Other actions of desipramine and imipramine may contribute to the overall efficacy.

Cell biology of Smad2/3 linker region phosphorylation in vascular smooth muscle

Publisher: Wiley

Date: 25-07-2012

DOI: 10.1111/J.1440-1681.2011.05592.X

Abstract: The transforming growth factor (TGF)-β superfamily of ligands regulates a erse set of cellular functions. Transforming growth factor-β induces its biological effects through Type I and Type II transmembrane receptors that have serine/threonine kinase activities and weak tyrosine kinase activity. In vascular smooth muscle, TGF-β binds to the TGF-β Type II receptor (TβRII) at the cell surface, recruiting the Type I receptor (TβRI) to form a heterocomplex. Consequently, after phosphorylation and activation of TβRI, the transcription factors receptor activated (R-) Smad2 and Smad3 are recruited and activated through phosphorylation of C terminal residues. Overall, Smad2/3 and co-Smad4 have similar structures consisting of three regions an N-terminal MH1 domain, a C-terminal MH2 domain and a central linker region. Phosphorylation of the Smad linker region appears to have an important role in the regulation of Smad activity and function. The mitogen-activated protein kinase (MAPK) family, CDK2, CDK4 and calcium-calmodulin dependent kinase are the main kinases that phosphorylate sites in the linker region. The role of the linker region includes enabling the formation of Smad homo-oligomers and provision of phosphorylation sites for MAPK and other kinases. In some instances, linker region phosphorylation regulates the inhibition of the nuclear translocation of Smads. In the present review, we describe TGF-β signalling through Smad2/3 and the importance of the linker region in the regulation and expression of genes induced by TGF-β superfamily ligands in the context of vascular smooth muscle.

The possible role of the Akt signaling pathway in schizophrenia

Publisher: Elsevier BV

Date: 08-2012

DOI: 10.1016/J.BRAINRES.2012.06.032

Abstract: Serine/threonine protein kinase v-akt murine thymoma viral oncogene homolog (Akt) is one of the survival kinases with multiple biological functions in the brain and throughout the body. Schizophrenia is one of the most devastating psychiatric disorders. Accumulating evidence has indicated the involvement of the Akt signaling pathway in the pathogenesis of this disorder. Genetic linkage and association studies have identified Akt-1 as a candidate susceptibility gene related for schizophrenia. The level of Akt-1 protein and its kinase activity decreased significantly both in white blood cells from schizophrenic patients and in postmortem brain tissue of schizophrenic patients. Consistent with these findings, alterations in the upstream and downstream pathways of Akt have also been found in many psychiatric disorders. Furthermore, both typical and atypical antipsychotic drugs modify the Akt signaling pathway in a variety of conditions relative to schizophrenia. In addition as a survival kinase, Akt participates in neurodevelopment, synaptic plasticity, protein synthesis and neurotransmission in the central nervous system. It is thought that reduced activity of phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway could at least partially explain the cognitive impairment, synaptic morphologic abnormality, neuronal atrophy and dysfunction of neurotransmitter signaling in schizophrenia. In addition, reduced levels of Akt may increase the effects of risk factors on neurodevelopment, attenuate the effects of growth factors on neurodevelopment and reduce the response of patients to antipsychotic agents. More recently, the role of Akt signaling in the functions of schizophrenia susceptibility genes such as disrupted-in-schizophrenia 1 (DISC-1), neuregulin-1 (NRG-1) and dysbindin-1 has been reported. Thus, Akt deficiency may create a context permissive for the expression of risk-gene effects in neuronal morphology and function. This paper reviews the role of Akt in the pathophysiology of schizophrenia and as a potential therapeutic strategy targeting Akt.

Androgens: New Effects on Proteoglycan Biosynthesis and Its Consequences for Atherosclerosis

Publisher: Hindawi Limited

Date: 2005

DOI: 10.1100/TSW.2005.75

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Publisher: Springer Science and Business Media LLC

Date: 03-11-2012

DOI: 10.1007/S00018-012-1194-Z

Thrombin-mediated Proteoglycan Synthesis Utilizes Both Protein-tyrosine Kinase and Serine/Threonine Kinase Receptor Transactivation in Vascular Smooth Muscle Cells

Publisher: Elsevier BV

Date: 03-2013

DOI: 10.1074/JBC.M112.400259

Polyhalogenated biphenyls and phenobarbital: Evaluation as inducers of drug metabolizing enzymes in the sheepshead, Archosargus probatocephalus

Publisher: Elsevier BV

Date: 08-1981

DOI: 10.1016/0009-2797(81)90022-3

Abstract: Several doses of Aroclor 1254 (polychlorinated biphenyl (PCB) mixture), Firemaster FF1 (polybrominated biphenyl (PBB) mixture), 2,2',4,4',5,5'-hexabromobiphenyl (HBB), 3,3',4,4',5,5'-hexachlorobiphenyl (HCB) and phenobarbital (PB) were administered to the marine fish sheepshead (Archosargus probatocephalus). The PCB and PBB mixtures caused induction of hepatic microsomal benzo[a]pyrene hydroxylase (AHH), 7-ethoxycoumarin O-deethylase (7-EC) and 7-ethoxyresorufin O-deethylase (ERF) activities, but not benzphetamine N-demethylase (BND), epoxide hydrolase (EH) or glutathione S-transferase (GSH-T) activities. This induction pattern is typical of that caused by polycyclic aromatic hydrocarbons (PAH) in fish and mammals or by tetrachlorodibenzo-p-dioxin (TCDD) in mammals. The extent of induction of AHH-activity and cytochrome P-450 content was higher when experiments were carried out in summer (water temperature 25 +/- 4 degrees C) than in winter (water temperature 11 +/- 3 degrees C). Firemaster FF1 (15 mg/kg) induced fish for at least 56 days in both summer and winter at which time the liver concentrations of PBB were in the ppm range. PCB concentrations in the ppm range have been found in fish from polluted lakes and seas, thus we may expect that environmental exposure to PCB is sufficient to induce hepatic mixed function oxidase (MFO) activities. The PCB isomer 3,3'4,4'5,5'-HCB, which induces the same spectrum of hepatic drug-metabolizing activities as TCDD and PAH in rats, had a broadly similar effect in the sheepshead. Another purified isomer, 2,2',4,4',5,5'-HBB, which induces the same enzymes as PB in rats, had no effect on drug-metabolizing activities in sheepshead. PB was also without effect on sheepshead hepatic drug-metabolizing enzymes, although a typical narcotic effect was produced in PB-treated sheepshead. Our studies provide further evidence that drug-metabolizing activities in fish liver are readily induced by chemicals like TCDD or PAH, but we fail to demonstrate induction after treatment of sheepshead with inducers of the PB type.

Multiple Growth Factors, But Not VEGF, Stimulate Glycosaminoglycan Hyperelongation in Retinal Choroidal Endothelial Cells

Publisher: Ivyspring International Publisher

Date: 2016

DOI: 10.7150/IJBS.16134

Cardiovascular actions and therapeutic potential of tanshinone IIA

Publisher: Elsevier BV

Date: 2012

DOI: 10.1016/J.ATHEROSCLEROSIS.2011.06.041

Abstract: Tanshinone IIA (TS), a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge (Danshen), has been clinically used in Asian countries for the prevention and treatment of coronary heart disease. Recently, the pharmacological properties of TS in the cardiovascular system have attracted great interest. Emerging experimental studies and clinical trials have demonstrated that TS prevents atherogenesis as well as cardiac injury and hypertrophy. In atherosclerosis, TS acts by inhibiting LDL oxidation, monocyte adhesion to endothelium, smooth muscle cell migration and proliferation, macrophage cholesterol accumulation, proinflammatory cytokine expression and platelet aggregation. TS has some activity and potential to stabilize atherosclerotic plaques. The cardioprotective effects of TS are mainly related to its anti-oxidant and anti-inflammatory actions. In this review, we focus on the protective effects and the mechanism of action of TS in the cardiovascular system, and provide a novel perspective on clinical use of TS.

Smad2 linker region phosphorylation is an autonomous cell signalling pathway: Implications for multiple disease pathologies

Publisher: Elsevier BV

Date: 04-2020

DOI: 10.1016/J.BIOPHA.2020.109854

Abstract: This review will cover the signalling pathways leading to the phosphorylation of the Smad linker region independent of Smad carboxy terminal phosphorylation. Characterising Smad linker region as a signalling pathway in its own right will encourage comprehensive signalling studies to provide solutions for successful discovery and exploitation of drug targets. The review describes Smad transcription factor signalling distinct from Transforming Growth Factor (TGF)-β signalling. Novel signalling pathways represent new drug targets where these pathways are known to be involved in fibrosis, cancer and cardiovascular disease.

Epidemiology, Public Health and Health Management

Publisher: Wiley

Date: 10-2013

DOI: 10.1111/1440-1681.12170_10

Temperature-dependent disposition of [14C]benzo(a)pyrene in the spiny lobster, Panulirus argus

Publisher: Elsevier BV

Date: 02-1985

DOI: 10.1016/0041-008X(85)90332-1

Abstract: [14C]Benzo(a)pyrene (BP) (1 mg/kg) was administered by intracardiac injection to groups of spiny lobsters which were killed at various times up to 7 weeks after dosing. Tissues and fluids were evaluated for BP-derived radioactivity. Two studies were conducted in successive summer and winter seasons, when seawater temperatures throughout were 26.5 to 29.0 and 13.5 to 16.5 degrees C, respectively. Highest concentrations of BP-derived radioactivity were found in the hepatopancreas, stomach, intestine, intestinal contents, and the green gland. After an initial distribution phase, the dose was lost from the lobsters in a log linear manner. The elimination half-lives for overall elimination of BP-derived radioactivity were 1.11 weeks in the warmer (summer) and 2.25 weeks in the colder (winter) water. Similarly, for in idual organs, elimination was more rapid in the warmer water. For the hepatopancreas, green gland, intestine, and tail muscle, respective t1/2 values (week) were 1.02, 1.26, 1.71, and 1.42 in the summer and 2.50, 1.50, 5.04, and 2.11 in the winter. There was no suggestion of tissue accumulation of BP-derived radioactivity. HPLC analysis of hepatopancreas s les showed that, in summer, unmetabolized BP concentrations fell rapidly, accounting for only 5% of the total label in the hepatopancreas by 3 days. The fall in unmetabolized BP was accompanied by approximately equal increases in the percentages of both polar metabolites and conjugates. Although the time curve for metabolism of BP in the hepatopancreas was not studied in winter, the metabolic capacity was such that, by 3 days after the dose, only 5% of the 14C present in hepatopancreas was unmetabolized BP. Thus, it appears that, for this dose of BP, the more rapid elimination of 14C in summer was due to a more rapid excretion of metabolites, and not to increased metabolism of BP.

Total Synthesis of the Cyclic Depsipeptide YM-280193, a Platelet Aggregation Inhibitor

Publisher: American Chemical Society (ACS)

Date: 15-01-2015

DOI: 10.1021/OL503507G

Abstract: The first total synthesis of YM-280193, a cyclic depsipeptide that inhibits the ADP-induced aggregation of human platelets, is described. The monomer and dipeptide fragments were prepared using conventional chemistry and subsequently assembled by Fmoc-solid-phase peptide synthesis (Fmoc-SPPS). A late-stage novel bis-alkylation-elimination of cysteine on-resin was employed to introduce the unnatural N-methyldehydroalanine moiety. The final step involved execution of a key macrolactamization reaction between the hindered unnatural N,O-dimethylthreonine and β-hydroxyleucine residues.

Peptidyl‐prolyl isomerases: Functionality and potential therapeutic targets in cardiovascular disease

Publisher: Wiley

Date: 12-01-2015

DOI: 10.1111/1440-1681.12335

Abstract: Peptidyl-prolyl cis/trans isomerases (PPIases) are a conserved group of enzymes that catalyse the conversion between cis and trans conformations of proline imidic peptide bonds. These enzymes play critical roles in regulatory mechanisms of cellular function and pathophysiology of disease. There are three different classes of PPIases and increasing interest in the development of specific PPIase inhibitors. Cyclosporine A, FK506, rapamycin and juglone are known PPIase inhibitors. Herein, we review recent advances in elucidating the role and regulation of the PPIase family in vascular disease. We focus on peptidyl-prolyl cis/trans isomerase NIMA-interacting 1 (Pin1), an important member of the PPIase family that plays a role in cell cycle progression, gene expression, cell signalling and cell proliferation. In addition, Pin1 may be involved in atherosclerosis. The unique role of Pin1 as a molecular switch that impacts on multiple downstream pathways necessitates the evaluation of a highly specific Pin1 inhibitor to aid in potential therapeutic drug discovery.

The effects of endogenous phospholipase A2 activation on beta adrenoceptor function in cardiac cells

Publisher: Elsevier BV

Date: 11-1983

DOI: 10.1016/0022-2828(83)90335-8

Abstract: The effects of endogenous phospholipase A2 activation by melittin on components of the beta adrenoceptor linked adenylate cyclase system were examined in cultured cardiac cells. Exposure of cardiac cells for one hour to melittin concentrations ranging from 0.125 microgram/ml to 5.0 micrograms/ml induced a concentration dependent hydrolysis of radioactively labelled phospholipids and loss of lysophospholipids from the cell membrane. Melittin concentrations of 2.5 micrograms/ml or greater markedly attenuated the isoprenaline induced rise in cyclic AMP. In vitro studies using cell homogenates suggest that phospholipase A2 activation by the higher concentration of melittin (5 micrograms/ml) partially uncoupled the beta adrenoceptor from adenylate cyclase. Beta adrenoceptor number estimated by 125I-iodohydroxybenzylpindolol specific binding as well as the affinity of isoprenaline for these binding sites were unaffected by melittin pre-exposure. The percentage stimulation of adenylate cyclase by sodium fluoride or guanylylimidodi-phosphate was not significantly affected by activation of endogenous phospholipase A2. Phosphodiesterase activity in the soluble fraction of cell homogenates increased marginally (9%, P = 0.05) in cells exposed to melittin. These results suggest that activation of endogenous phospholipase A2 within the sarcolemma can modulate the activity of the beta adrenoceptor linked adenylate cyclase system of intact cardiac cells. The reduced beta adrenoceptor responsiveness of the cells appears to be primarily due to an alteration in coupling between the beta adrenoceptor and the guanine nucleotide binding protein components of the adenylate cyclase system and not between the latter and the catalytic subunit.

Emerging Lipoprotein-Related Therapeutics for Patients with Diabetes

Publisher: Springer New York

Date: 17-07-2013

DOI: 10.1007/978-1-4614-7554-5_23

Inhibitors of hepatic mixed-function oxidases. 4. Effects of benzimidazole and related compounds on aryl hydrocarbon hydroxylase activity from phenobarbitone and 3-methylcholanthrene induced rats

Publisher: American Chemical Society (ACS)

Date: 06-1982

DOI: 10.1021/JM00348A003

Abstract: A series of 2-n-alkylbenzimidazoles inhibited cytochrome P-450 dependent aryl hydrocarbon hydroxylase (AHH) and aminopyrine N-demethylase (APDM) activities in phenobarbitone (PB) induced rat liver microsomes. 2-Un-decylbenzimidazole was the most potent compound in the series, having I50 values of 1.8 X 10(-5) and 1.5 X 10(-5) M against AHH and APDM activities, respectively. Inhibitory activity increased with increasing carbon chain length of the 2-substituent. Regression analysis showed that there was an apparent relationship between inhibitory activity and hydrophobicity (expressed as the octanol/water partition coefficient) for the inhibition of both AHH and APDM activities in PB-induced rat liver microsomes. In contrast, these compounds showed little or no inhibitory activity toward cytochrome P-448 dependent AHH activity in hepatic microsomes from 3-methylcholanthrene (3-MC) treated rats. Two 5,6-dimethylbenzimidazoles showed slight inhibitory activity and naphtho[2,3:4',5']imidazole was only threefold less active toward 3-MC-induced (I50 = 2.6 X 10(-4) M) than PB-induced (I50 = 8.4 X 10(-5) AHH activity. These results suggest that for nitrogen heterocycles there may be a relationship of increasing polycyclic size and increasing inhibitory activity toward AHH activity in 3-MC induced rat liver microsomes.

Troglitazone, but not rosiglitazone, inhibits Na/H exchange activity and proliferation of macrovascular endothelial cells

Publisher: Elsevier BV

Date: 05-2001

DOI: 10.1016/S1056-8727(01)00141-6

Abstract: Diabetes is associated with a high level of mortality due to cardiovascular disease resulting from accelerated coronary artery atherosclerosis. A current focus for investigation of atherosclerotic mechanisms is the vascular endothelium since physical or functional injury may represent an initiating step for atherogenesis. Thiazolidinediones (TZDs) are the newest class of drugs for the treatment of insulin resistance and its metabolic consequences they are peroxisome proliferator-activating receptor (PPAR)-gamma ligands that act as insulin-sensitizing agents. We are interested in the contribution of direct vascular actions to the clinical utility of these agents. We investigated the effect troglitazone and rosiglitazone on endothelial cell proliferation in low- and high-glucose media and further explored their action on the ubiquitous membrane transport system, the Na/H exchanger (NHE), which has been implicated in regulating the growth of vascular cells. Experiments were conducted in cultured bovine aortic endothelial cells (BAECs). Cell proliferation was assessed by cell counting, and NHE activity was determined in cells loaded with the pH-sensitive fluorescent dye, 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein, acetoxymethyl ester (BCECF-AM). Troglitazone caused a dose-dependent inhibition of endothelial cell proliferation with approximately 50% inhibition at 10 microM. Troglitazone inhibited endothelial cell proliferation with similar potency under low- (5 mM) and high-glucose (25 mM) concentrations. Rosiglitazone had no significant effect on endothelial cell proliferation at concentrations of up to 100 microM under low- or high-glucose concentrations. The NHE inhibitor, 3-metlylsulfonyl-4-piperidinobenzoyl guanidine (HOE 694), caused dose dependent inhibition of BAEC proliferation, which was independent of the media glucose concentration. Acute exposure of cells to troglitazone (10 microM) and rosiglitazone (30 microM) during recovery from acidosis showed slight but significant (P .05) effect by rosiglitazone. Exposure of cells to either drug for 24 h revealed no chronic regulation of NHE activity. Our data demonstrate that troglitazone has similar actions in endothelial cells as in vascular smooth muscle. The absence of rosiglitazone effects, a more potent PPAR-gamma activator, suggests that the observed actions of troglitazone may be at least partially independent of PPAR-gamma. The effects of troglitazone and rosiglitazone on endothelial cell proliferation and NHE activity, although contrasting, are consistent with a central signalling role of this transporter in cell proliferation.

Endothelin-1 (ET-1) stimulates carboxy terminal Smad2 phosphorylation in vascular endothelial cells by a mechanism dependent on ET receptors and de novo protein synthesis

Publisher: Oxford University Press (OUP)

Date: 12-2016

DOI: 10.1111/JPHP.12654

Abstract: G protein-coupled receptor (GPCR) agonists through their receptors can transactivate protein tyrosine kinase receptors such as epidermal growth factor receptor and serine/threonine kinase receptors most notably transforming growth factor (TGF)-β receptor (TβRI). This signalling mechanism represents a major expansion in the cellular outcomes attributable to GPCR signalling. This study addressed the role and mechanisms involved in GPCR agonist, endothelin-1 (ET-1)-mediated transactivation of the TβRI in bovine aortic endothelial cells (BAECs). The in-vitro model used BAECs. Signalling intermediate phospho-Smad2 in the carboxy terminal was detected and quantified by Western blotting. ET-1 treatment of BAECs resulted in a time and concentration-dependent increase in pSmad2C. Peak phosphorylation was evident with 100 nm treatment of ET-1 at 4–6 h. TβRI antagonist, SB431542 inhibited ET-1-mediated pSmad2C. In the presence of bosentan, a mixed ETA and ETB receptor antagonist ET-1-mediated pSmad2C levels were inhibited. The ET-mediated pSmad2C was blocked by the protein synthesis inhibitor, cycloheximide. In BAECs, ET-1 via the ETB receptor is involved in transactivation of the TβRI. The transactivation-dependent response is dependent upon de novo protein synthesis.

PDGF β-Receptor Kinase Activity and ERK1/2 Mediate Glycosaminoglycan Elongation on Biglycan and Increases Binding to LDL

Publisher: The Endocrine Society

Date: 07-07-2010

DOI: 10.1210/EN.2010-0027

Abstract: The initiation of atherosclerosis involves the subendothelial retention of lipoproteins by proteoglycans (PGs). Structural characteristics of glycosaminoglycan (GAG) chains on PGs influence lipoprotein binding and are altered adversely by platelet-derived growth factor (PDGF). The signaling pathway for PDGF-mediated GAG elongation via the PDGF receptor (PDGFR) was investigated. In human vascular smooth muscle cells, PDGF significantly increased 35S-sulfate incorporation into PGs and GAG chain size. PGs from PDGF-stimulated cells showed increased binding low-density lipoprotein (P & 0.001) in gel mobility shift assays. Knockdown of PDGFRβ using small interfering RNA demonstrated that PDGF mediated changes in PGs via PDGFRβ. GAG synthesis and hyperelongation was blocked by inhibition of receptor tyrosine kinase autophosphorylation site Tyr857 activity using Ki11502 or imatinib. Downstream signaling to GAG hyperelongation was mediated through ERK MAPK and not phosphatidylinositol-3 kinase or phospholipase Cγ. In high-fat-fed apolipoprotein E−/− mice, inhibition of PDGFRβ activity by imatinib reduced aortic total lipid staining area by 35% (P & 0.05). Inhibition of PDGFRβ tyrosine kinase activity leads to inhibition of GAG synthesis on vascular PGs and aortic lipid area in vivo. PDGFRβ and its signaling pathways are potential targets for novel therapeutic agents to prevent the earliest stages atherosclerosis.

Activatable magnetic resonance nanosensor as a potential imaging agent for detecting and discriminating thrombosis

Publisher: Royal Society of Chemistry (RSC)

Date: 2018

DOI: 10.1039/C8NR05095C

Abstract: MRI T 1 / T 2 switchable nanosensor discriminates thrombus age by exhibiting a T 1 signal on fresh thrombus while showing a T 2 signal on aged thrombus. The nanosensor is also labelled with 5-TAMRA for optical imaging.

Evaluation of the potential synergism of imatinib-related poly kinase inhibitors using growth factor stimulated proteoglycan synthesis as a model response

Publisher: Oxford University Press (OUP)

Date: 17-02-2016

DOI: 10.1111/JPHP.12530

Abstract: Tyrosine kinase inhibitors were the first class of smart drugs being specifically designed to inhibit a disease causing target. There is a very important but unresolved question as whether or not the overall therapeutic role of an in idual tinib results from an action at its primary target, a single most likely, tyrosine kinase, or from the combined or aggregate action at the multiple targets which each tinib addresses. We selected a series of ten tinibs (gefitinib, sunitinib, lapatinib, erlotinib, imatinib, sorafenib, axitinib, vanitinib, bosutinib, dasatinib) with various known targets and investigated their activities in the inhibition of proteoglycan synthesis and GAG hyperelongation stimulated by a tyrosine kinase receptor agonist, platelet derived growth factor (PDGF) and for contrast, a serine/threonine kinase receptor agonist, TGF β and some downstream signalling pathways. The inhibitory activity varied from little to total inhibition. The actions of the tinibs were directed more towards inhibition of the tyrosine kinase, PDGF receptor signalling pathway compared to the TGF β. There was no suggestion of any synergistic effect arising from inhibition of multiple kinases as the most potent compound, dasatinib, is known to inhibit the broadest spectrum of kinases.

TGF-β stimulates biglycan synthesis via p38 and ERK phosphorylation of the linker region of Smad2

Publisher: Springer Science and Business Media LLC

Date: 07-03-2010

DOI: 10.1007/S00018-010-0315-9

Abstract: Transforming growth factor (TGF)-beta treatment of human vascular smooth-muscle cells increases the expression of biglycan and causes marked elongation of its glycosaminoglycan (GAG) chains. We investigated the role of MAP kinases and Smad transcription factors in this response. TGF-beta-stimulated phosphorylation of p38, ERK, and JNK as well as Smad2 at both its carboxy terminal (phospho-Smad2C) and in the linker region (phospho-Smad2L). Pharmacological inhibition of ERK and p38 blocked TGF-beta-mediated GAG elongation and expression of biglycan whereas inhibition of JNK had no effect. Inhibition of ERK and p38 but not JNK attenuated the effect of TGF-beta to increase phospho-Smad2L. High levels of phospho-Smad2L were detected in a nuclear fraction of TGF-beta treated cells. Thus, MAP kinase signaling through ERK and p38 and via phosphorylation of the linker region of Smad2 mediates the effects of TGF-beta on biglycan synthesis in vascular smooth-muscle cells.

Smad and p38 MAP Kinase-mediated Signaling of Proteoglycan Synthesis in Vascular Smooth Muscle

Publisher: Elsevier BV

Date: 03-2008

DOI: 10.1074/JBC.M703125200

Characterisation of Ki11502 as a potent inhibitor of PDGF β receptor-mediated proteoglycan synthesis in vascular smooth muscle cells

Publisher: Elsevier BV

Date: 2010

DOI: 10.1016/J.EJPHAR.2009.09.066

Abstract: Platelet-derived growth factor (PDGF) receptor signalling is implicated in cardiovascular diseases such as atherosclerosis and restenosis. PDGF expression levels are elevated in atherosclerotic lesions and play a key role in migration and proliferation of vascular smooth muscle cells in the neointima. PDGF stimulates glycosaminoglycan elongation on vascular proteoglycans biglycan and decorin, a process implicated in the aetiology of atherosclerosis. We investigated the ability of the specific kinase inhibitor Ki11502 to inhibit PDGF beta receptor phosphorylation and proteoglycan synthesis in human vascular smooth muscle cells. Ki11502 inhibited PDGF-mediated tyrosine phosphorylation of the PDGF beta receptor autophosphorylation site and at least six other receptor-associated proteins. Ki11502 also caused a concentration-dependent inhibition of PDGF-stimulated [(3)H]-thymidine incorporation. Total proteoglycan synthesis was assessed as incorporation of [(35)S]-sulfate. PDGF-induced a two-fold increase in [(35)S]-sulfate incorporation into proteoglycans secreted over 24h and was inhibited in a concentration-dependent manner by Ki11502. PDGF treatment resulted in a statistically significant (P<0.01) increase in total proteoglycan core protein secretion. Treatment of cells with Ki11502 (300 nM) had no effect on basal core protein secretion and completely abolished the PDGF-stimulated component. Analysis of isolated cleaved glycosaminoglycan chains by size-exclusion chromatography demonstrated that PDGF stimulated the synthesis and secretion of proteoglycans with elongated glycosaminoglycan chains and this effect was inhibited by Ki11502. Inhibition was also seen in the length of xyloside-glycosaminoglycan chains. The results demonstrate that Ki11502 is a potent and selective inhibitor of PDGF beta receptor phosphorylation, proliferation and proteoglycan synthesis in human vascular smooth muscle cells.

Smad2-dependent glycosaminoglycan elongation in aortic valve interstitial cells enhances binding of LDL to proteoglycans

Publisher: Elsevier BV

Date: 03-2013

DOI: 10.1016/J.CARPATH.2012.07.002

Abstract: Calcific aortic valve disease is a progressive condition that shares some common pathogenic features with atherosclerosis. Transforming growth factor-β1 is a recognized mediator of atherosclerosis and is expressed in aortic valve lesions. Transforming growth factorβ1 stimulates glycosaminoglycan elongation of proteoglycans that is associated with increased lipid binding. We investigated the presence of transforming growth factor-β1 and downstream signaling intermediates in diseased human aortic valves and the effects of activated transforming growth factor-β1 receptor signaling on aortic valve interstitial cell proteoglycan synthesis and lipid binding as a possible mechanism for the initiation of the early lesion of calcific aortic valve disease. Diseased human aortic valve leaflets demonstrated strong immunohistochemical staining for transforming growth factor-β1 and phosphorylated Smad2/3. In primary porcine aortic valve interstitial cells, Western blots showed that transforming growth factor-β1 stimulated phosphorylation in both the carboxy and linker regions of Smad2/3, which was inhibited by the transforming growth factor-β1 receptor inhibitor SB431542. Gel electrophoresis and size exclusion chromatography demonstrated that SB431542 decreased transforming growth factor-β1-mediated [(35)S]-sulfate incorporation into proteoglycans in a dose-dependent manner. Further, in proteoglycans derived from transforming growth factor-β1-treated valve interstitial cells, gel mobility shift assays demonstrated that inhibition of transforming growth factor-β1 receptor signaling resulted in decreased lipid binding. Classic transforming growth factor-β1 signaling is present in human aortic valves in vivo and contributes to the modification of proteoglycans expressed by valve interstitial cells in vitro. These findings suggest that transforming growth factor-β1 may promote increased low-density lipoprotein binding in the early phases of calcific aortic valve disease.

Corrigendum to: Cardiovascular actions and therapeutic potential of tanshinone IIA [Atherosclerosis 220 (2012) 3–10]

Publisher: Elsevier BV

Date: 04-2012

DOI: 10.1016/J.ATHEROSCLEROSIS.2012.01.014

Regulation of vascular smooth muscle cell growth by amiloride-sensitive pHi control mechanisms

Publisher: Elsevier BV

Date: 07-1990

DOI: 10.1016/0014-2999(90)94387-D

Endothelial Dysfunction in Atherosclerotic Cardiovascular Diseases and Beyond: From Mechanism to Pharmacotherapies

Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)

Date: 04-06-2021

DOI: 10.1124/PHARMREV.120.000096

Treatment of atherosclerotic plaque: perspectives on theranostics

Publisher: Oxford University Press (OUP)

Date: 25-04-2019

DOI: 10.1111/JPHP.13092

Abstract: Atherosclerosis, a progressive condition characterised by the build-up of plaque due to the accumulation of low-density lipoprotein and fibrous substances in the damaged arteries, is the major underlying pathology of most cardiovascular diseases. Despite the evidence of the efficacy of the present treatments for atherosclerosis, the complex and poorly understood underlying mechanisms of atherosclerosis development and progression have prevented them from reaching their full potential. Novel alternative treatments like usage of nanomedicines and theranostics are gaining attention of the researchers worldwide. This review will briefly discuss the current medications for the disease and explore potential future developments based on theranostics nanomaterials that may help resolve atherosclerotic cardiovascular disease. Various drugs can slow the effects of atherosclerosis. They include hyperlipidaemia medications, anti-platelet drugs, hypertension and hyperglycaemia medications. Most of the theranostic agents developed for atherosclerosis have shown the feasibility of rapid and noninvasive diagnosis, as well as effective and specific treatment in animal models. However, there are still some limitation exist in their structure design, stability, targeting efficacy, toxicity and production, which should be optimized in order to develop clinically acceptable nanoparticle based theronostics for atherosclerosis. Current medications for atherosclerosis and potential theranostic nanomaterials developed for the disease are discussed in the current review. Further investigations remain to be carried out to achieve clinical translation of theranostic agents for atherosclerosis.

Urokinase plasminogen activator induces smooth muscle cell migration: key role of growth factor‐like domain

Publisher: Wiley

Date: 08-09-1997

DOI: 10.1016/S0014-5793(97)00993-9

Abstract: We defined the role of urokinase plasminogen activator (uPA) and its growth factor-like domain (GFD) in stimulating smooth muscle cell (SMC) migration. Recombinant uPA (r-uPA) stimulated migration approximately 3-fold whilst the recombinant uPA mutant containing an altered GFD (r-uPAmut) was ineffective. Both uPA variants bound to the same high affinity receptor in a competitive manner. FGF-2- and PDGF-BB-induced migration was also dependent on uPA, their effects being antagonized by addition of a uPA-neutralizing antibody or the r-uPAmut. Thus r-uPA is chemotactic for SMC and stimulation of cell migration by PDGF-BB and FGF-2 is dependent on uPA. The GFD of uPA is essential for its chemotactic effects.

Novel iron oxide-cerium oxide core-shell nanoparticles as a potential theranostic material for ROS related inflammatory diseases

Publisher: Royal Society of Chemistry (RSC)

Date: 2018

DOI: 10.1039/C8TB00022K

Abstract: Novel iron oxide–cerium oxide core–shell theranostic nanoparticles for MRI and ROS scavenging effects.

Teaching Politics and International Relations

Publisher: Palgrave Macmillan UK

Date: 2012

DOI: 10.1057/9781137003560

Inhibitory Activity of Clinical Thiazolidinedione Peroxisome Proliferator Activating Receptor-γ Ligands Toward Internal Mammary Artery, Radial Artery, and Saphenous Vein Smooth Muscle Cell Proliferati

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 27-05-2003

DOI: 10.1161/01.CIR.0000074040.31731.96

Abstract: Background— The proliferation of vascular smooth muscle cells (VSMCs) is a known response to arterial injury that is an important part of the process of restenosis and atherosclerosis. People with diabetes have an increased risk of cardiovascular disease resulting from accelerated coronary atherosclerosis. The newest drugs for Type 2 diabetes are thiazolidinediones, which are insulin-sensitizing peroxisome proliferator activating receptor-γ (PPARγ) ligands. We investigated the antiproliferative effects of troglitazone, rosiglitazone, and pioglitazone on VSMCs derived from the three vascular beds used for coronary artery by-pass grafting: the internal mammary and radial artery and saphenous veins. Methods and Results— The three vessels yielded proliferating cells of slightly differing morphology. Inhibition of cell proliferation was assessed by cell counting and cell cycle studies by Western blotting for phosphorylated retinoblastoma protein. All three thiazolidinediones showed inhibitory potency toward cell proliferation with a potency troglitazone rosiglitazone≈pioglitazone, and this potency profile was maintained toward the growth factor and insulin-stimulated phosphorylation of the retinoblastoma protein, which controls cell cycle progression. Conclusion— The inhibitory potency of clinical thiazolidinediones toward different vascular sources is dependent on the in idual thiazolidinedione and very little on the vascular source.

Angiotensin II and noradrenaline increase PDGF-BB receptors and potentiate PDGF-BB stimulated DNA synthesis in vascular smooth muscle

Publisher: Elsevier BV

Date: 1990

DOI: 10.1016/0006-291X(90)90848-H

Abstract: The effects of angiotensin II and noradrenaline were examined on PDGF-BB and PDGF-AB induced mitogenesis in primary cultures of rat aortic smooth muscle. Incubation of the smooth muscle with either angiotensin II or noradrenaline potentiated the submaximal but not maximal mitogenic effects of PDGF-BB but not PDGF-AB. These effects on PDGF-BB stimulated mitogenesis correlated with an increase in receptor number specific for this homodimer when the smooth muscle was incubated with either angiotensin II or noradrenaline. Mitogenic concentrations of PDGF-AB did not interact with this PDGF receptor subtype. These results indicate that the mitogenic effects of PDGF-AB and -BB are elicited via different PDGF receptor subtypes. Angiotensin II and noradrenaline potentiate the mitogenic effects of PDGF-BB by increasing the steady state concentrations of membrane receptors for this homodimer.

Platelet-derived growth factor-stimulated versican synthesis but not glycosaminoglycan elongation in vascular smooth muscle is mediated via Akt phosphorylation

Publisher: Elsevier BV

Date: 05-2014

DOI: 10.1016/J.CELLSIG.2014.01.019

Abstract: Proteoglycans are associated with the initiation of atherosclerosis due to their binding of apolipoproteins on lipid particles leading to retention in the vessel wall. The signaling pathways through which growth factors regulate the synthesis and structure of proteoglycans are potential therapeutic targets. Platelet-derived growth factor (PDGF) is present in atherosclerotic plaques and activates phosphorylation of the serine/threonine kinase Akt. We have investigated the role of Akt in the signaling pathways for proteoglycan core protein expression and elongation of glycosaminoglycan chains on proteoglycans secreted by human vascular smooth muscle cells. The pharmacological inhibitor of Akt phosphorylation, SN30978, blocked PDGF stimulated phosphorylation of Akt. SN30978 caused concentration dependent inhibition of PDGF stimulated radiosulfate incorporation into secreted proteoglycans and the response was blocked by the PDGF receptor antagonists Ki11502 and imatinib. Analysis of the size of the biglycan molecules by SDS-PAGE showed that PDGF increased the apparent size of biglycan but this effect on glycosaminoglycan chain elongation was blocked by Ki11502 but not by SN30978. PDGF also stimulated total protein core protein synthesis assessed as (35)S-methionine/cysteine incorporation and specifically the expression of versican mRNA. Both of these responses were blocked by SN30978. This data shows that PDGF-stimulated proteoglycan core protein synthesis but not glycosaminoglycan chain elongation is mediated via Akt phosphorylation. These data identify potential pathways for the development of agents which can pharmacologically regulate in idual components of the synthesis of proteoglycans.

REGULATION AND ROLE OF UROKINASE PLASMINOGEN ACTIVATOR IN VASCULAR REMODELLING

Publisher: Wiley

Date: 09-1996

DOI: 10.1111/J.1440-1681.1996.TB01177.X

Abstract: 1. Urokinase plasminogen activator (uPA) is produced and secreted by multiple vascular cell types, thus influencing the processes and the extent to which the vasculature is remodelled during the development of the intima or a neointima and during hypertrophy and angiogenesis. 2. Urokinase plasminogen activator mRNA expression is up- and down-regulated by growth factors, cytokines and steroids. Urokinase plasminogen activator is secreted as a single chain inactive form that may be proteolytically converted to active or inactive forms. Targeting of proteolytic activity may occur via focalized expression of uPA and its cell surface receptors (uPAR). Proteolytic activity is also controlled through the often co-ordinated expression of specific inhibitors. 3. A proteolytic cascade involving uPA provides its major role in tissue remodelling through the primary degradation of extracellular matrix and secondarily through the activation of transforming growth factor-beta or release from the matrix of basic fibroblast growth factor. In addition, uPA secreted by growth factor-stimulated vascular cells may contribute to the chemotactic and mitogenic responses ascribed to the growth factor and recent evidence strongly suggests that uPA has direct biological actions on vascular cells. 4. The cell surface binding of uPA via its growth factor-like domain to uPAR localizes and activates the protease, but may also initiate transmembrane signalling of biological responses, including migration/invasion and proliferation. As the uPAR lacks intracellular signalling domains, the signals may be transduced via interactions between uPA/uPAR and more classical signalling receptors. The mechanism by which uPA may be involved in cell signalling is yet to be elucidated.

MULTIPLE GROWTH ABNORMALITIES IN VASCULAR SMOOTH MUSCLE FROM SPONTANEOUSLY HYPERTENSIVE RATS

Publisher: Wiley

Date: 05-1991

DOI: 10.1111/J.1440-1681.1991.TB01454.X

Abstract: 1. In tissue culture the growth characteristics of aortic smooth muscle cells isolated from spontaneously hypertensive rats (SHR) were compared with those of normotensive Wistar-Kyoto (WKY) rats. 2. Aortic smooth muscle cells from SHR exhibit enhanced proliferation when grown in the presence of low (1%) and moderate (5%) concentrations of fetal calf serum. 3. Cell quiescence in cultures of smooth muscle from SHR becomes apparent at cell densities approximately 20% higher than in cultures from WKY rats. 4. These different growth characteristics of smooth muscle between the two strains of rats may contribute to the early pre-hypertensive development of vascular hypertrophy in the SHR.

Effects of Alterations in Cell Phenotype and Hypokalemia on Sodium-Potassium Pump Activity in Rabbit Vascular Smooth Muscle

Publisher: Informa UK Limited

Date: 1985

DOI: 10.3109/10641968509073610

Abstract: We investigated in cell culture, how alterations in phenotype accompanying proliferation of rabbit aortic smooth muscle and chronic hypokalemia could affect the Na,K pump. Total rubidium-86 uptake as well as ouabain and frusemide-sensitive uptake into cells was measured in physiological salts solution (PSS), PSS containing 5% foetal calf serum and PSS containing foetal calf serum plus 15 microM monensin. In physiological salts solution 90% of the rubidium-86 uptake into contractile or synthetic state cells was frusemide-sensitive and less than 8% ouabain-sensitive. Total and frusemide-sensitive rubidium-86 uptakes, measured in PSS or PSS containing foetal calf serum were similar in cells cultured and maintained in the contractile phenotype, cells in the synthetic phenotype and those which had recently reverted from the synthetic to contractile phenotype. When cells were sodium loaded in the presence of monensin and foetal calf serum, ouabain-sensitive rubidium-86 uptake was 50% higher in cells which were maintained in culture in the contractile phenotype. Frusemide-sensitive rubidium-86 uptake was similar in each cell phenotype. To examine how cell culture in hypokalemic media would affect the Na,K pump, we determined ouabain-sensitive rubidium-86 uptake in the presence of monensin plus foetal calf serum in cells incubated for 24 hours in low and normal potassium containing culture media. Ouabain-sensitive uptake was 20% higher in cells cultured in a 0.76 mM potassium medium than in those cultured in 5.4 mM potassium medium. Frusemide-sensitive rubidium-86 uptake was unaffected. These results demonstrate that 'maximal' Na,K pump activity in sodium-loaded cells is reduced when cells change from the contractile to synthetic phenotype. This reduction appears only very slowly reversible when cells revert from the synthetic to contractile phenotype. Prolonged hypokalemia increases 'maximal' activity of the Na,K pump.

Emerging Lipoprotein-Related Therapeutics for Patients with Diabetes

Publisher: Springer International Publishing

Date: 2023

DOI: 10.1007/978-3-031-26681-2_30

Inhibition of rat hepatic microsomal aminopyrine N-demethylase activity by benzimidazole derivatives. Quantitative structure-activity relationships

Publisher: American Chemical Society (ACS)

Date: 08-1982

DOI: 10.1021/JM00350A002

Abstract: Eight-two benzimidazole derivatives have been prepared and tested for the ability to inhibit cytochrome P-450 mediated enzyme activity (aminopyrine N-demethylase) from phenobarbitone-induced rat hepatic microsomes. Using physicochemical parameters and multiple regression analysis, we derived a quantitative structure-activity relationship (QSAR) that describes up to 87% of the data variance in terms of hydrophobic and electronic effects and the molar refractivity of the substituent in the 2-position of the benzimidazole ring.

Endothelin-1 signalling in vascular smooth muscle: Pathways controlling cellular functions associated with atherosclerosis

Publisher: Elsevier BV

Date: 08-2008

DOI: 10.1016/J.ATHEROSCLEROSIS.2008.03.006

Abstract: Atherosclerosis is the primary ischaemic vascular condition underlying a majority of cardiovascular disease related deaths. Endothelin-1 is a vasoactive peptide agent upregulated in atherosclerosis and in conjunction with its G protein-coupled receptors exerts erse actions on all cells of the vasculature in particular vascular smooth muscle cells (VSMC). The effects of endothelin-1 include cell proliferation, migration and contraction, and the induction of extracellular matrix components and growth factors. VSMC as the major component of the neointima in atherosclerotic plaques accordingly play a key role in atherogenesis. In this review we examine classic and novel signalling pathways activated by endothelin-1 in VSMC (including phospholipase C, adenylate cyclase, Rho kinase, transactivation of receptor tyrosine kinases, mitogen activated protein kinase cascades and beta-arrestin) and their likely impact on the development and progression of atherosclerosis.

Endothelin-1 Actions on Vascular Smooth Muscle Cell Functions As a Target for the Prevention of Atherosclerosis

Publisher: Bentham Science Publishers Ltd.

Date: 07-2008

DOI: 10.2174/157016108784911966

Abstract: The formation and progression of atherosclerotic plaques followed by rupture, thrombus formation and vessel blockage leads to ischemic tissue damage and the clinical condition underlying most cardiovascular disease. Therapeutic agents for the prevention of atherosclerosis have all targeted epidemiologically-identified and relatively easily measured risk factors (e.g. lipids and blood pressure). This strategy has proven somewhat effective but is of less than optimal efficacy as rates of cardiovascular disease remain high. Treatment targeting the mechanisms of atherosclerosis in the vessel wall is a conceptually attractive proposition to complement the risk factor directed strategy. Vascular smooth muscle cells (VSMC) are the major cellular component of the vascular media and migration and proliferation leads to the formation of the neointima the development of which renders the vessels particularly sensitive to atherosclerosis. Numerous hormones and growth factors act on VSMC to cause migration, proliferation and the secretion of extracellular matrix and modulation or dysfunction of these processes is the most likely cause of atherosclerosis. Endothelin-1 (ET-1) is a 21 amino acid peptide that acts on 7 transmembrane G protein coupled receptors to elicit a plethora of responses that can modulate the behaviour of VSMCs and thus impact on the development of atherosclerosis. ET-1 is elevated in atherosclerotic plaques. People with diabetes have accelerated atherosclerosis and also show elevated plasma levels of ET-1. This review addresses the actions of ET-1 on VSMC and the signalling pathways through which it mediates its effects as the latter represent potential therapeutic targets for the prevention of atherosclerosis.

Signalling pathways regulating galactosaminoglycan synthesis and structure in vascular smooth muscle: Implications for lipoprotein binding and atherosclerosis

Publisher: Elsevier BV

Date: 07-2018

DOI: 10.1016/J.PHARMTHERA.2018.02.005

Abstract: Atherosclerosis commences with the trapping of low density lipoproteins (LDLs) in blood vessels by modified proteoglycans (PGs) with hyperelongated glycosaminoglycan (GAG) chains. GAG chain synthesis and growth factor mediated hyperelongation regulates the composition and size of PGs in a manner that would cause low density lipoprotein (LDLs) retention in vessel wall. Galactosaminoglycans are a class of GAGs, commonly observed on PGs. Multiple enzymes are involved in galactosaminoglycan biosynthesis. Galactosaminoglycan synthesis is regulated by various signalling pathways which are amenable to pharmacological manipulation to treat atherosclerosis. Receptor mediated signalling pathways including protein tyrosine kinase receptors (PTKRs), serine/threonine kinase receptors (S/TKRs) and G-protein coupled receptors (GPCRs) pathways regulate galactosaminoglycan synthesizing enzyme expression. Increased expression of these enzymes modify galactosaminoglycan chain structure by making them hyperelongated. This review focuses on the signalling pathways regulating the expression of genes involved in galactosaminoglycan synthesis and modification. Furthermore, there are multiple other processes for inhibiting the interactions between LDL and galactosaminoglycans such as peptide mimetics of ApoB100 and anti-galactosaminoglycan antibodies and the therapeutic potential of these strategies is also addressed.

IGF-1 Signaling via the PI3K/Akt Pathway Confers Neuroprotection in Human Retinal Pigment Epithelial Cells Exposed to Sodium Nitroprusside Insult

Publisher: Springer Science and Business Media LLC

Date: 23-10-2014

DOI: 10.1007/S12031-014-0448-7

Abstract: The pathological increase in the levels of the second messenger nitric oxide (NO) in the vitreous cavity and retina leads to injury and cell death of the retinal pigment epithelium (RPE) cells and eventually may contribute to the occurrence and development of diabetic retinopathy. In this study, we developed a cellular model of retinopathy using D407 cells (a human RPE cell line) exposed to sodium nitroprusside (SNP) and investigated the protective effect of the insulin-like growth factor-1 (IGF-1) towards this insult. Cell death and apoptosis were examined by the methyl thiazolyl tetrazolium assay and Hoechst staining, respectively. Specific inhibitors were used and phosphorylation of relevant signaling proteins was determined by Western blotting. SNP, in a concentration-dependent fashion, increased the production of reactive oxygen species (ROS) and lipid peroxidation process causing cell death by apoptosis of D407 cells. IGF-1, in a time- and dose-dependent manner, conferred protection towards SNP-mediated insult. Both phosphatidylinositol-3-kinase rotein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) were activated by IGF-1 in relation to the protective effect. Blockade of the PI3K/Akt pathway abolished the protective effect of IGF-1 whereas inhibition of the MAPK pathway was ineffective. SNP decreased the phosphorylation of Akt in the cells while IGF-1 reversed this inhibitory effect. These results indicate that the protective effect of IGF-1 on D407 exposed to SNP insult is mediated by the PI3K/Akt pathway. This proposal may be exploited in the clinic to improve the viability of insulted retinal cells for maintaining physiological vision.

Transforming growth factor-β regulation of proteoglycan synthesis in vascular smooth muscle: Contribution to lipid binding and accelerated atherosclerosis in diabetes

Publisher: Wiley

Date: 21-11-2010

DOI: 10.1111/J.1753-0407.2010.00089.X

Abstract: Atherosclerosis is accelerated in the setting of diabetes, but the factors driving this phenomenon remain elusive. Hyperglycemia leads to elevated levels of transforming growth factor (TGF)-β and TGF-β has been implicated as a factor in atherosclerosis. Given the established association between hyperglycemia and elevated TGF-β, it is plausible that elevated TGF-β levels in diabetes play a pathogenic role in the development of accelerated atherosclerosis. TGF-β is a potent regulator of extracellular matrix synthesis, including many actions on proteoglycan synthesis that lead to increased binding to low-density lipoprotein and therefore potentially increased lipid retention in the vessel wall and accelerated atherosclerosis. TGF-β signals through the canonical TGF-β receptor I-mediated phosphorylation of Smad transcription factors and TGF-β signaling is also known to involve, positively and negatively, interactions with the mitogen-activated protein kinase pathways. The focus of the present review is on the effects of TGF-β on proteoglycan synthesis in vascular smooth muscle and particularly the signaling pathways through which TGF-β exerts its effects, because those pathways may be therapeutic targets for the prevention of pathological modifications in the proteoglycan component of the vessel wall in the vascular diseases of diabetes.

Animal models for assessing the impact of natural products on the aetiology and metabolic pathophysiology of Type 2 diabetes

Publisher: Elsevier BV

Date: 05-2017

DOI: 10.1016/J.BIOPHA.2017.03.010

Abstract: Type 2 diabetes mellitus is a complex and heterogeneous disorder which in its most common manifestation arises from insulin resistance and later insulin insufficiency. Type 2 diabetes is characterised by impaired insulin sensitivity and diagnosed as hyperglycaemia. Because of its cardiovascular consequences, Type 2 diabetes represents one of the world's leading causes of mortality and morbidity. Drug discovery and development are required to produce better ways to prevent, treat and manage diabetes and its complications. Diabetes is a human, not an animal disease, so animals do not get Type 2 diabetes. However there are animal models which are variously suitable for the investigation of new agents for the treatment of Type 2 diabetes. In this Review we have examined the various models that are available for the study of natural products with a focus on models (genetic, nutritional and spontaneous) for the metabolic abnormities of diabetes. These models are also relevant to the investigation of Western medicines for the treatment of diabetes. A suitable experimental model plays an important role in drug discovery for translational studies leading to increased understanding of the molecular basis and management of diabetes.

Mechanical strain stimulates a mitogenic response in coronary vascular smooth muscle cells via release of basic fibroblast growth factor

Publisher: Oxford University Press (OUP)

Date: 11-2001

DOI: 10.1016/S0895-7061(01)02189-6

Abstract: Mechanical strain has been shown to induce mitogenesis in a rat neonatal vascular smooth muscle (VSM) cell line in a response mediated predominantly by transcription, expression, and release of platelet-derived growth factor (PDGF). We examined the effect of cyclic mechanical strain and growth factor production on mitogenic response in ovine coronary artery smooth muscle cells. Vascular smooth muscle cells were cultured from explants of left anterior descending (LAD) coronary arteries from young sheep. Cells for experiments were grown on wells with silicone-elastomer bottoms, and subjected to strain (60 cycles/min) using a vacuum actuated strain device. Tritiated thymidine incorporation was used as a measure of DNA synthesis. Cell membrane damage was assessed with differentially permeable nuclear staining dyes. We observed an increase in tritiated thymidine incorporation in response to strain with a temporal response identical to that observed in response to exogenous growth factors (PDGF-BB and basic fibroblast growth factor [bFGF]). Supernatant medium obtained from stretched cells induced a twofold increase in DNA synthesis in unstretched cells. The mitogenic response was abolished by monoclonal antibodies to bFGF, but not by antibodies to PDGF-AB. Studies of fluorescent dye exclusion indicated the stretching protocol caused no cell membrane damage. Thus, mechanical strain is an important stimulus for growth factor release in coronary VSM cells. The mitogenic response is mediated by release of bFGF.

Smad linker region phosphorylation in the regulation of extracellular matrix synthesis

Publisher: Springer Science and Business Media LLC

Date: 04-09-2010

DOI: 10.1007/S00018-010-0514-4

Abstract: The canonical TGF-β signalling pathway involves Smad transcription factors through direct serine phosphorylation of the carboxy termini, nuclear translocation and regulation of transcription by receptor-regulated (R)-Smad complexes. Smads can also be phosphorylated in the linker region most prominently by the action of mitogen-activated protein (MAP) kinases, which in turn have been activated by TGF-β or a multitude of other growth factors and hormones. Linker region phosphorylation can prevent nuclear translocation of Smads and inhibit TGF-β signalling, potentially leading to oncogenesis. However, some evidence has revealed that linker region phosphorylated Smads can be translocated to the nucleus where they regulate transcription particularly of the synthesis of extracellular matrix molecules. Matrix molecules such as collagen and proteoglycans are involved in diseases such a fibrosis and atherosclerosis, respectively, and the involvement of linker region phosphorylation may represent a new therapeutic target.

Stereoselective Reduction of 1‐O‐Isopropyloxygenipin Enhances Its Neuroprotective Activity in Neuronal Cells from Apoptosis Induced by Sodium Nitroprusside

Publisher: Wiley

Date: 06-04-2014

DOI: 10.1002/CMDC.201400051

Abstract: Genipin is a Chinese herbal medicine with both neuroprotective and neuritogenic activity. Because of its unstable nature, efforts have been to develop more stable genipin derivatives with improved biological activities. Among the new compounds reported in the literature, (1R)-isopropyloxygenipin (IPRG001) is a more stable but less active compound compared with the parent, genipin. Here, two new IPRG001 derivatives generated by stereoselective reduction of the C6 =C7 double bond were synthesized. The 1R and 1S isomers of (4aS,7S,7aS)-methyl-7-(hydroxymethyl)-1-isopropoxy-1,4a,5,6,7,7a-hexahydrocyclopenta[c]pyran-4-carboxylate (CHR20 and CHR21) were shown to be very stable both in high-glucose cell culture medium and in mice serum at 37 °C. Evaluation using an MTT assay and Hoechst staining showed that CHR20 and CHR21 promote the survival of rat adrenal pheochromocytoma (PC12) and retinal neuronal (RGC-5) cells from injury induced by sodium nitroprusside (SNP). The neuroprotective effects of CHR20 and CHR21 were greater than both isomers of IPRG001, the parent compounds. These results indicate that reduction of 1-O-isopropyloxygenipin enhances its neuroprotective activity without affecting its stability.

Artemisinin inhibits glycosaminoglycan chain synthesizing gene expression but not proliferation of human vascular smooth muscle cells

Publisher: Elsevier BV

Date: 11-2020

DOI: 10.1016/J.BBRC.2020.08.013

Insulin-like growth factor-1 induces the phosphorylation of PRAS40 via the PI3K/Akt signaling pathway in PC12 cells

Publisher: Elsevier BV

Date: 05-2012

DOI: 10.1016/J.NEULET.2012.03.068

Abstract: Insulin-like growth factor-1 (IGF-1) is a polypeptide tropic factor that plays an important role in the survival and differentiation of both neuronal and non-neuronal cells. Numerous studies have demonstrated that IGF-1 promotes neuronal cell survival via the PI3K/Akt signaling pathway. Proline-rich Akt substrate of 40kDa (PRAS40) is a recently discovered downstream target of Akt. However, the relationship between IGF-1 and PRAS40 is not known. In this study, we characterized the phosphorylation of PRAS40 induced by IGF-1 in PC12 cells and explored the signaling pathway responsible for the effect of IGF-1. IGF-1 induced the phosphorylation of Akt at Thr473 and PRAS40 at Thr246 in PC12 cells. The phosphorylation of Akt and PRAS40 induced by IGF-1 (100ng/ml) was inhibited by the phosphatidylinositide 3-kinase (PI3K) specific inhibitor LY294002 (50μM), while no inhibitory effect was observed for a MAPK kinase pathway specific inhibitor PD98059 nor a p38 MAPK inhibitor PD169316, suggesting that the phosphorylation of PRAS40 induced by IGF-1 is mediated by the PI3K pathway in PC12 cells and primary cultured neurons. In further support this hypothesis, an Akt kinase specific inhibitor, Akt inhibitor VIII, attenuated IGF-1-induced phosphorylation of PRAS40 at the concentration that blocked the phosphorylation of Akt induced by IGF-1. Taken together, these data demonstrate that IGF-1 stimulates the phosphorylation of PRAS40 at Thr246 in neuronal cells and the effect of IGF-1 is mediated, at least in part, by the PI3K/Akt signaling pathway.

Transforming growth factor-β signalling: Role and consequences of Smad linker region phosphorylation

Publisher: Elsevier BV

Date: 10-2013

DOI: 10.1016/J.CELLSIG.2013.06.001

Abstract: Transforming growth factor-β (TGF-β) is a secreted homodimeric protein that plays an important role in regulating various cellular responses including cell proliferation and differentiation, extracellular matrix production, embryonic development and apoptosis. Disruption of the TGF-β signalling pathway is associated with erse disease states including cancer, renal and cardiac fibrosis and atherosclerosis. At the cell surface TGF-β complex consists of two type I and two type II transmembrane receptors (TβRI and TβRII respectively) which have serine/threonine kinase activity. Upon TGF-β engagement TβRII phosphorylates TβRI which in turn phosphorylates Smad2/3 on two serine residues at their C-terminus which enables binding to Smad4 to form heteromeric Smad complexes that enter the nucleus to initiate gene transcription including for extracellular matrix proteins. TGF-β signalling is also known to activate other serine/threonine kinase signalling that results in the phosphorylation of the linker region of Smad2. The Smad linker region is defined as the domain which lies between the MH1 and MH2 domains of a Smad protein. Serine/threonine kinases that are known to phosphorylate the Smad linker region include mitogen-activated protein kinases, extracellular-signal regulated kinase, Jun N-terminal kinase and p38 kinase, the tyrosine kinase Src, phosphatidylinositol 3'-kinase, cyclin-dependent kinases, rho-associated protein kinase, calcium calmodulin-dependent kinase and glycogen synthase kinase-3. This review will cover the role of Smad linker region phosphorylation downstream of TGF-β signalling in vascular cells. Key factors including the identification of the kinases that phosphorylate in idual Smad residues, the upstream agents that activate these kinases, the cellular location of the phosphorylation event and the importance of the linker region in regulation and expression of genes induced by TGF-β are covered.

Platelet-derived Growth Factor Differentially Regulates the Expression and Post-translational Modification of Versican by Arterial Smooth Muscle Cells through Distinct Protein Kinase C and Extracellul

Publisher: Elsevier BV

Date: 03-2010

DOI: 10.1074/JBC.M109.088674

Insulin Resistance and Atherosclerosis

Publisher: The Endocrine Society

Date: 05-2006

DOI: 10.1210/ER.2005-0007

Abstract: The epidemic of obesity in the developed world over the last two decades is driving a large increase in type 2 diabetes and consequentially setting the scene for an impending wave of cardiovascular morbidity and mortality. It is only now being recognized that the major antecedent of type 2 diabetes, insulin resistance with its attendant syndrome, is the major underlying cause of the susceptibility to type 2 diabetes and cardiovascular disease. In metabolic tissues, insulin signaling via the phosphatidylinositol-3-kinase pathway leads to glucose uptake so that in insulin resistance a state of hyperglycemia occurs other factors such as dyslipidemia and hypertension also arise. In cardiovascular tissues there are two pathways of insulin receptor signaling, one that is predominant in metabolic tissues (mediated by phosphatidylinositol-3-kinase) and another being a growth factor-like pathway (mediated by MAPK) the down-regulation of the former and continued activity of the latter pathway leads to atherosclerosis. This review addresses the metabolic consequences of the insulin resistance syndrome, its relationship with atherosclerosis, and the impact of insulin resistance on processes of atherosclerosis including insulin signaling in cells of the vasculature.

Clinical Thiazolidinediones as PPAR&#947; Ligands with the Potential for the Prevention of Cardiovascular Disease in Diabetes

Publisher: Bentham Science Publishers Ltd.

Date: 05-2006

DOI: 10.2174/157339906776818622

Abstract: Thiazolidinediones (TZDs) are PPARgamma ligands and the newest class of agents in routine clinical practice for the treatment of hyperglycemia in type 2 diabetes. The prime reason for treating hyperglycemia and related aspects of the metabolic syndrome is to prevent accelerated cardiovascular disease (CVD) in diabetes. The formation and subsequent rupture of atherosclerotic "plaques", establishes CVD as the major cause of premature mortality in diabetes. Metabolically, TZDs act as insulin sensitizers resulting in improved glucose uptake, lower blood glucose and reduced hyperinsulinemia, however, they also appear to have beneficial direct vascular actions. TZDs have a range of actions directly on vascular cells and the predominance of the reported actions is potentially beneficial. TZDs inhibit vascular smooth muscle cell proliferation, inhibit the expression of adhesion molecules and modify the structure of vascular proteoglycans in a manner that results in reduced lipid binding. These actions manifest as reduced lipid deposition in the vessels of animals with experimental diabetes and atherosclerosis. Early clinical data indicates that TZDs may prevent or delay CVD including atherosclerosis and restenosis following coronary angiography. TZDs may be the first class of oral hypoglycemic agents with significant anti atherogenic effects to combat one of the major complications of diabetes.

Androgens Stimulate Human Vascular Smooth Muscle Cell Proteoglycan Biosynthesis and Increase Lipoprotein Binding

Publisher: The Endocrine Society

Date: 04-2005

DOI: 10.1210/EN.2004-1242

Abstract: Vascular smooth muscle cell (VSMC) proliferation and proteoglycan biosynthesis are two critical contributors to the development of atherosclerosis. We investigated the effects of specific androgens, androstenedione, dihydrotestosterone, and testosterone, on proteoglycan biosynthesis in human VSMC derived from internal mammary arteries. Vascular SMCs were metabolically labeled with [(35)S]sulfate or [(35)S]methionine/cysteine to assess glycosaminoglycans (GAGs) or proteoglycan core protein, respectively. The electrophoretic migration of radiolabeled proteoglycans was assessed by SDS-PAGE. Proteoglycan-low density lipoprotein (LDL) interactions were assessed using LDL affinity columns. Treatment of VSMCs with androstenedione (100 nm), dihydrotestosterone (10 nm), or testosterone (100 nm) increased [(35)S]sulfate incorporation into GAGs by 24.8% (P < 0.05), 22% (P < 0.05), and 32.5% (P < 0.05), respectively. Treatment of VSMCs with testosterone did not alter [(35)S]methionine/cysteine incorporation into proteoglycan core protein, suggesting that the effect of testosterone was associated with an increase in GAG length. Dihydrotestosterone (10 nm) and testosterone (100 nm) treatment of VSMCs resulted in the synthesis of biglycan and decorin that showed reduced electrophoretic mobility by SDS-PAGE, indicating an increase in GAG length. The effect of testosterone treatment on [(35)S]sulfate incorporation and GAG length was reversed by pretreatment of VSMCs with flutamide (1 mum), an androgen receptor antagonist. Proteoglycans from VSMCs treated with testosterone showed 11% (P < 0.01) higher binding capacity to LDL compared with proteoglycans from untreated cells. These results suggest a possible proatherogenic action of androgens through an elongation of GAG chains on proteoglycans in an androgen receptor-dependent manner.

Regulation of the atherogenic properties of vascular smooth muscle proteoglycans by oral anti-hyperglycemic agents

Publisher: Elsevier BV

Date: 03-2007

DOI: 10.1016/J.JDIACOMP.2006.03.003

Abstract: The present study aimed to investigate the actions of several classes of oral hypoglycemic agents [e.g., sulfonylureas (SUs), biguanides (BGs) and thiazolidinediones (TZDs)] in an in vitro model of lipid binding based on the "response to retention" hypothesis of atherogenesis. The incorporation of [(35)S]-SO(4) into proteoglycans synthesized by human vascular smooth muscle cells (VSMCs) was assessed by cetylpyridinium chloride (CPC) precipitation method, proteoglycan electrophoretic mobility was evaluated by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), and binding to low-density lipoprotein (LDL) was assessed by gel mobility shift assay (GMSA). The SUs evaluated showed no effect on [(35)S]-SO(4) incorporation into proteoglycans. Only one BG, phenformin, caused a concentration-related inhibition of proteoglycan synthesis under basal conditions and in the presence of transforming growth factor-beta1 (TGF-beta1), caused by an inhibition of proteoglycan core protein synthesis secondary to a reduction in total protein synthesis. However, neither metformin nor phenformin (30-300 micromol/l) had any effect on the electrophoretic mobility of proteoglycans. The TZDs--troglitazone (TRO), rosiglitazone (ROS), and pioglitazone (PIO) (10, 30, and 30 micromol/l, respectively)--inhibited proteoglycan biosynthesis and stimulated total proteoglycan core protein synthesis, while TRO alone inhibited overall protein synthesis. All three TZDs moderately reduced the electrophoretic mobility of synthesized proteoglycans assessed by SDS-PAGE, reduced the sizes of cleaved glycosaminoglycan (GAG) chains assessed by size exclusion chromatography, and significantly reduced binding to LDL. The data indicate that TZDs show anti-atherogenic actions through the modification of proteoglycan structure, leading to a possible reduction in lipid retention in the vessel wall.

Inhibitors of hepatic mixed function oxidases—V. Inhibition of aminopyrine N-demethylation and enhancement of aniline hydroxylation by benzoxazole derivatives

Publisher: Elsevier BV

Date: 05-1982

DOI: 10.1016/0006-2952(82)90690-6

Thrombin Stimulation of Proteoglycan Synthesis in Vascular Smooth Muscle Is Mediated by Protease-activated Receptor-1 Transactivation of the Transforming Growth Factor β Type I Receptor

Publisher: Elsevier BV

Date: 08-2010

DOI: 10.1074/JBC.M109.092767

Forkhead box protein O3 suppresses uveal melanoma development by increasing the expression of Bcl‑2‑like protein 11 and cyclin‑dependent kinase inhibitor 1B

Publisher: Spandidos Publications

Date: 07-12-2017

DOI: 10.3892/MMR.2017.8215

Abstract: Forkhead box protein O3 (FoxO3a) is a forkhead box family transcription factor which serves an important role in a number of biological functions, including tumor growth. A previous study indicated that FoxO3a serves a role in insulin like growth factor‑induced growth, migration and invasion of uveal melanoma (UM) cells however, whether FoxO3a is associated with the development and formation of UM remains unknown. In the present study, the role of FoxO3a in UM development and formation was investigated by modulating the expression of FoxO3a in a human UM cell line. The results of the present study demonstrated that FoxO3a overexpression in UM cells inhibited cell proliferation and promoted cellular apoptosis, leading to an accumulation of cells at the G1 cell cycle phase. Western blot analysis demonstrated that FoxO3a overexpression increased the transcription and protein expression of Bcl‑2‑like protein 11 and cyclin‑dependent kinase inhibitor 1B, and inhibited cyclin D1 transcription and expression. The opposite effects were observed when FoxO3a was knocked down in UM cells. The results of the present study indicated that FoxO3a may exhibit a negative role in UM development and formation, which is consistent with its role as a tumor suppressor.

Genetic and physiological association of diabetes susceptibility with raised Na+/H+ exchange activity.

Publisher: Proceedings of the National Academy of Sciences

Date: 21-06-1994

DOI: 10.1073/PNAS.91.13.5898

Abstract: Insulin-dependent diabetes mellitus is a multigenic autoimmune disease, for which one of the best animal models is the nonobese diabetic (NOD) mouse strain. In both humans and NOD mice, major histocompatibility complex genes are implicated as risk factors in the disease process. Other susceptibility genes are also involved, and a number have been mapped in the mouse to specific chromosomal locations. To identify further susceptibility genes, diabetic backcross mice, produced after crossing NOD/Lt to the nondiabetic strains SJL and C57BL/6 (B6), were examined for markers not previously associated with disease susceptibility. Linkage was found to loci on chromosomes 4 and 14. Of the candidate loci on chromosome 4, the gene encoding the Na+/H+ exchanger-1, Nhe-1, was the most likely, since the NOD allele was different from that of both nondiabetic strains. NOD lymphocytes were found to have a higher level of Na+/H+ exchange activity than lymphocytes from either B6 or SJL mice. Since the chromosome 4 susceptibility gene is recessive, the B6 allele should prevent diabetes. This prediction was tested in fourth-generation backcross mice, selected for retention of the B6 allele at Nhe-1. Mice homozygous for Nhe-1 developed diabetes after cyclophosphamide treatment, but heterozygotes were largely protected from disease. These results implicate the Na+/H+ exchanger (antiporter) in the development of type 1 diabetes and may provide a screening test for at-risk in iduals as well as offering prospects for disease prevention.

Integrating the GPCR transactivation-dependent and biased signalling paradigms in the context of PAR1 signalling

Publisher: Wiley

Date: 16-02-2016

DOI: 10.1111/BPH.13398

Calcific Aortic Valve Disease and Hypertension

Publisher: Bentham Science Publishers Ltd.

Date: 05-2008

DOI: 10.2174/157340208784245884

Hyperelongated biglycan: the surreptitious initiator of atherosclerosis

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2008

DOI: 10.1097/MOL.0B013E32830DD7C4

Suramin inhibits PDGF-stimulated receptor phosphorylation, proteoglycan synthesis and glycosaminoglycan hyperelongation in human vascular smooth muscle cells

Publisher: Oxford University Press (OUP)

Date: 24-04-2013

DOI: 10.1111/JPHP.12064

Abstract: Suramin is a polysulfonated naphthylurea with antiparasitic and potential antineoplastic activity. Suramin's pharmacological actions, which have not yet been fully elucidated, include antagonism of the action of platelet-derived growth factor (PDGF) at its receptor. We investigated the effects of suramin on PDGF-stimulated proteoglycan synthesis. Human vascular smooth muscle cells (VSMCs) were incubated in the presence and absence of PDGF and suramin with [3H]thymidine or 35SO4 as radiolabels. Mitogenic response was determined by [3H]thymidine incorporation. PDGFβ receptor phosphorylation was assessed by western blotting. Proteoglycan size and glycosaminoglycan chain synthesis and size were determined by sodium dodecyl sulfate–polyacrylamide gel electrophoresis. The Alphascreen phosphotyrosine assay kit was used to investigate PDGFβ receptor tyrosine kinase inhibition by suramin. Suramin decreased PDGF-stimulated proliferation, proteoglycan synthesis and GAG chain hyperelongation. Suramin also directly inhibited PDGFβ receptor kinase activity as well as PDGFβ receptor phosphorylation in intact VSMCs. These data show that inhibition of PDGFβ receptor phosphorylation in intact cells is necessary to define a fully active PDGF antagonist. They also confirm that PDGFβ receptor kinase activity is necessary for PDGF-mediated atherogenic changes in proteoglycan synthesis and support efforts to develop PDGFβ receptor antagonists as potential anti-atherosclerotic agents.

An Investigation of Sodium Fusidate and Recombinant Cytochrome P450 Enzymes Inhibition In-Vitro

Publisher: Bentham Science Publishers Ltd.

Date: 29-09-2016

DOI: 10.2174/1872312810666160607015045

Abstract: Sodium fusidate (fusidic acid) is an antimicrobial agent that is used in the treatment of staphylococcal and streptococcal infections. Several case reports have noted a drug interaction between sodium fusidate and CYP3A4 metabolised statins, leading to statin toxicity. It is unclear whether sodium fusidate has the potential to cause interactions with other cytochrome P450 enzymes. To investigate the effects of sodium fusidate on recombinant cytochrome P450 enzymes (1A2, 2C9, 2C19, 2D6 and 3A4) in-vitro. A range of sodium fusidate concentrations (0.1µM, 1µM, 10µM, 100µM, 300µM, 1000µM and 10000µM) were tested to examine its activity on rCYP1A2, rCYP2C9, rCYP2C19, rCYP2D6 and rCYP3A4 using a luminescent assay with a luciferin substrate. Sodium fusidate inhibited all enzymes at tested concentrations which are relevant to those likely to be achieved in clinical practice. Further, sodium fusidate was found to be a time-dependent inhibitor of all the tested isoenzymes, with the exception of rCYP2C9. These findings suggest that there is a potential for sodium fusidate to cause drug interactions when used with other agents that are substrates for rCYP1A2, rCYP2C9, rCYP2C19, rCYP2D6 or rCYP3A4. Understanding the basis of this potential drug interaction will assist in safer use of sodium fusidate in clinical practice.

The effect of PPAR ligands to modulate glucose metabolism alters the incorporation of metabolic precursors into proteoglycans synthesized by human vascular smooth muscle cells

Publisher: Informa UK Limited

Date: 2008

DOI: 10.1080/13813450802181013

Abstract: PPAR ligands are important effectors of energy metabolism and can modify proteoglycan synthesis by vascular smooth muscle cells (VSMCs). Describing the cell biology of these important clinical agents is important for understanding their full clinical potential, including toxicity. Troglitazone (10 microM) and fenofibrate (30 microM) treatment of VSMCs reduces ((35)S)-sulphate incorporation into proteoglycans due to a reduction of glycosaminoglycan (GAG) chain length. Conversely, under physiological glucose conditions (5.5 mM), the same treatment increases ((3)H)-glucosamine incorporation into GAGs. This apparent paradox is the consequence of an increase in the intracellular ((3)H)-galactosamine specific activity from 48.2 +/- 3.2 microCi/ micromol to 90.7 +/- 11.0 microCi/ micromol (P < 0.001) and 57.1 +/- 2.6 microCi/ micromol (P < 0.05) when VSMCs were treated with troglitazone and fenofibrate, respectively. The increased specific activity observed with troglitazone (10 microM) treatment correlates with a two-fold increase in glucose consumption, while fenofibrate (50 microM) treatment showed a modest (14.6%) increase in glucose consumption. We conclude that the sole use of glucosamine precursors to assess GAG biosynthesis results in misleading conclusions when assessing the effect of PPAR ligands on VSMC proteoglycan biosynthesis.

VASCULAR LOCALIZATION OF THE 11β‐HYDROXYSTEROID DEHYDROGENASE TYPE II ENZYME

Publisher: Wiley

Date: 07-1996

DOI: 10.1111/J.1440-1681.1996.TB02776.X

Abstract: 1. The enzyme 11β‐hydroxysteroid dehydrogenase type II (11βHSD2) confers specificity on the non‐specific mineralocorticoid receptor by converting cortisol to cortisone. 2. We have examined the localization of this enzyme in the human skin, myocardium and saphenous vein by immuno‐histochemical techniques. 3. High amounts of 11βHSD2 immunoreactivity were found in smooth muscle cells in the arterioles of the skin, heart and saphenous vein. Lower amounts of staining were also found in longitudinal and concentric smooth muscle cells lining the lumen of the saphenous vein.

Targeting LOX‐1 in atherosclerosis and vasculopathy: current knowledge and future perspectives

Publisher: Wiley

Date: 11-2018

DOI: 10.1111/NYAS.13984

Abstract: LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1 also known as OLR1) is the dominant receptor that recognizes and internalizes oxidized low-density lipoproteins (ox-LDLs) in endothelial cells. Several genetic variants of LOX-1 are associated with the risk and severity of coronary artery disease. The LOX-1-ox-LDL interaction induces endothelial dysfunction, leukocyte adhesion, macrophage-derived foam cell formation, smooth muscle cell proliferation and migration, and platelet activation. LOX-1 activation eventually leads to the rupture of atherosclerotic plaques and acute cardiovascular events. In addition, LOX-1 can be cleaved to generate soluble LOX-1 (sLOX-1), which is a useful diagnostic and prognostic marker for atherosclerosis-related diseases in human patients. Of therapeutic relevance, several natural products and clinically used drugs have emerged as LOX-1 inhibitors that have antiatherosclerotic actions. We hereby provide an updated overview of role of LOX-1 in atherosclerosis and associated vascular diseases, with an aim to highlighting the potential of LOX-1 as a novel theranostic tool for cardiovascular disease prevention and treatment.

(S)-[6]-Gingerol inhibits TGF-β-stimulated biglycan synthesis but not glycosaminoglycan hyperelongation in human vascular smooth muscle cells

Publisher: Oxford University Press (OUP)

Date: 27-03-2013

DOI: 10.1111/JPHP.12060

Abstract: (S)-[6]-Gingerol is under investigation for a variety of therapeutic uses. Transforming growth factor (TGF)-β stimulates proteoglycan synthesis, leading to increased binding of low-density lipoproteins, which is the initiating step in atherosclerosis. We evaluated the effects of (S)-[6]-gingerol on these TGF-β-mediated proteoglycan changes to explore its potential as an anti-atherosclerotic agent. Purified (S)-[6]-gingerol was assessed for its effects on proteoglycan synthesis by [35S]-sulfate incorporation into glycosaminoglycan chains and [35S]-Met/Cys incorporation into proteoglycans and total proteins in human vascular smooth muscle cells. Biglycan level was assessed by real-time quantitative polymerase chain reactions and the effects of (S)-[6]-gingerol on TGF-β signalling by assessment of the phosphorylation of Smads and Akt by western blotting. (S)-[6]-Gingerol concentration-dependently inhibited TGF-β-stimulated proteoglycan core protein synthesis, and this was not secondary to inhibition of total protein synthesis. (S)-[6]-Gingerol inhibited biglycan mRNA expression. (S)-[6]-Gingerol did not inhibit TGF-β-stimulated glycosaminoglycan hyperelongation or phosphorylation of Smad 2, in either the carboxy terminal or linker region, or Akt phosphorylation. The activity of (S)-[6]-gingerol to inhibit TGF-β-stimulated biglycan synthesis suggests a potential role for ginger in the prevention of atherosclerosis or other lipid-binding diseases. The signalling studies indicate a novel site of action of (S)-[6]-gingerol in inhibiting TGF-β responses.

Non-Mouse Models of Atherosclerosis: Approaches to Exploring the Translational Potential of New Therapies

Publisher: MDPI AG

Date: 26-10-2022

DOI: 10.3390/IJMS232112964

Abstract: Cardiovascular disease is the largest single cause of disease-related mortality worldwide and the major underlying pathology is atherosclerosis. Atherosclerosis develops as a complex process of vascular lipid deposition and retention by modified proteoglycans, endothelial dysfunction and unresolved chronic inflammation. There are a multitude of current therapeutic agents, most based on lowering plasma lipid levels, but, overall, they have a lower than optimum level of efficacy and many deaths continue to arise from cardiovascular disease world-wide. To identify and evaluate potential novel cardiovascular drugs, suitable animal models that reproduce human atherosclerosis with a high degree of fidelity are required as essential pre-clinical research tools. Commonly used animal models of atherosclerosis include mice (ApoE−/−, LDLR−/− mice and others), rabbits (WHHL rabbits and others), rats, pigs, hamster, zebrafish and non-human primates. Models based on various wild-type and genetically modified mice have been extensively reviewed but mice may not always be appropriate. Thus, here, we provide an overview of the advantages and shortcomings of various non-mouse animal models of atherosclerotic plaque formation, and plaque rupture, as well as commonly used interventional strategies. Taken together, the combinatorial selection of suitable animal models readily facilitates reproducible and rigorous translational research in discovering and validating novel anti-atherosclerotic drugs.

Siah2‐deficient mice show impaired skin wound repair

Publisher: Wiley

Date: 29-04-2013

DOI: 10.1111/WRR.12045

Abstract: Hypoxia is associated with the dermal wound healing process and hypoxia signaling is presumed to be crucial for normal wound repair. The Siah2 ubiquitin ligase controls the abundance of hypoxia-inducible factor-1 alpha, and loss of Siah2 results in destabilization of hypoxia-inducible factor-1 alpha under hypoxia. Utilizing Siah2(-/-) mice we demonstrate that cutaneous wound healing is impaired in these mice. Wounds in Siah2(-/-) mice heal slower and are associated with delayed induction of myofibroblast infiltration and reduced collagen deposition. This coincides with delayed angiogenesis and reduced macrophage infiltration into the wounds of Siah2(-/-) mice. We furthermore demonstrate that primary Siah2(-/-) dermal fibroblasts have reduced migratory capacities and produce less collagen than wild-type fibroblasts. Additionally, Siah2(-/-) fibroblasts showed conserved responses to transforming growth factor-β at the receptor level (pSmad 2C activation) but reduced responses downstream. Together, our data show, for the first time, that Siah2 is involved as a positive regulator in the wound healing response. Understanding the role of hypoxia signaling in tissue repair and fibrosis and interference with the hypoxia signaling pathway via regulation of Siah2 may provide new targets for clinical regulation of fibrosis and scarring.

High glucose potentiates mitogenic responses of cultured ovine coronary smooth muscle cells to platelet derived growth factor and transforming growth factor-β1

Publisher: Elsevier BV

Date: 02-2003

DOI: 10.1016/S0168-8227(02)00201-2

Abstract: Macrovascular complications in diabetes are associated with exaggerated growth responses of vascular smooth muscle cells. We studied the effect of high glucose media on the growth responses of vascular smooth muscle cells from the left anterior descending (LAD) coronary artery of young sheep. Experiments were conducted in DMEM containing 5.5 or 25 mmol/l glucose and mitogenic responses assessed by 3H-thymidine incorporation. In the absence of growth factors there was a slight and variable response to high glucose but the maximum response to platelet derived growth factor-bb (PDGF-bb) (100 ng/ml) was increased more than 2-fold. Transforming growth factor-beta1 (1 ng/ml) caused a 100% increase of the PDGF-bb response in both normal and high glucose media. The acute stimulatory effect of high glucose was not affected by pre-incubation of the cells for 24 h in the high glucose medium. The mitogenic response occurring in the presence of PDGF-bb and high glucose was totally inhibited by the tyrosine kinase inhibitors (imatinib and genistein) and could not be mimicked by increasing diacylglycerol in low glucose media with the diacylglycerol kinase inhibitor, R59949. In conclusion, high glucose, per se, only very weakly stimulates smooth muscle cell growth but it interacts positively to potentiate the responses to the vascular derived growth factors PDGF and TGF-beta1. The effect of high glucose is transduced via receptor tyrosine kinases and may not involve diacylglycerol that is subject to diacylglycerol kinase catabolism. The data provide explanations for the accelerated vascular smooth muscle cell proliferation in diabetes.

Another piece of cell biology in the puzzle of inflammation, glucose and diabetic vascular disease

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 03-2008

DOI: 10.1097/HJH.0B013E3282F4E35D

Impact of sleep apnea on sympathetic nervous system activity in heart failure

Publisher: Elsevier BV

Date: 04-2003

DOI: 10.1378/CHEST.123.4.1119

Abstract: To compare and establish the relevance of the relative degree of sympathetic nervous system activity (SNSA) in groups of patients with congestive heart failure (CHF) and obstructive sleep apnea (OSA), and in a control group. Elevated SNSA is a characteristic feature of CHF, as well as of OSA and nonhypercapnic central sleep apnea (CSA). OSA and CSA commonly occur with CHF however, the relative contribution of apnea-related hypoxemia and sleep fragmentation to the SNSA of patients with CHF is not known. This was a prospective, controlled, observational trial in which the overnight urinary norepinephrine (UNE) level, which is a measure of integrated overnight SNSA while asleep, was measured in 15 healthy male volunteers, 15 male OSA patients who did not have CHF, and 90 CHF patients (77 men). CHF patients also had right heart pressure measurements and then were grouped by the presence of sleep apnea. Compared with healthy in iduals, the mean (+/- SD) UNE level was significantly elevated in the OSA group and was even further elevated in the CHF group (13.4 +/- 5.6 vs 19.7 +/- 12.3 vs 32.2 +/- 20.2 nmol/mmol creatinine, respectively p < 0.001 [by analysis of variance]). Within the CHF group, the mean UNE levels were greatest in the CHF-CSA group compared with the CHF-OSA group and the CHF nonapnea group (43.9 +/- 24.1 vs 24.0 +/- 10.8 vs 22.4 +/- 8.9 nmol/mmol creatinine, respectively p < 0.001). Using a multivariate regression model, the variance of the UNE level in the CHF group was predicted, in descending order, by pulmonary capillary wedge pressure (14% variance), rapid eye movement sleep (8%), and the mean sleep pulse oximetry level (7%). Overnight SNSA is significantly greater in CHF patients than in OSA patients. Moreover, the hemodynamic severity of CHF contributes to the elevation of SNSA in CHF patients to a greater degree than apnea-related hypoxemia.

Factors affecting proteoglycan synthesis and structure that modify the interaction with lipoproteins

Publisher: Informa UK Limited

Date: 08-2009

DOI: 10.2217/CLP.09.37

Targeting protein modifications in metabolic diseases: molecular mechanisms and targeted therapies

Publisher: Springer Science and Business Media LLC

Date: 27-05-2023

DOI: 10.1038/S41392-023-01439-Y

Abstract: The ever-increasing prevalence of noncommunicable diseases (NCDs) represents a major public health burden worldwide. The most common form of NCD is metabolic diseases, which affect people of all ages and usually manifest their pathobiology through life-threatening cardiovascular complications. A comprehensive understanding of the pathobiology of metabolic diseases will generate novel targets for improved therapies across the common metabolic spectrum. Protein posttranslational modification (PTM) is an important term that refers to biochemical modification of specific amino acid residues in target proteins, which immensely increases the functional ersity of the proteome. The range of PTMs includes phosphorylation, acetylation, methylation, ubiquitination, SUMOylation, neddylation, glycosylation, palmitoylation, myristoylation, prenylation, cholesterylation, glutathionylation, S-nitrosylation, sulfhydration, citrullination, ADP ribosylation, and several novel PTMs. Here, we offer a comprehensive review of PTMs and their roles in common metabolic diseases and pathological consequences, including diabetes, obesity, fatty liver diseases, hyperlipidemia, and atherosclerosis. Building upon this framework, we afford a through description of proteins and pathways involved in metabolic diseases by focusing on PTM-based protein modifications, showcase the pharmaceutical intervention of PTMs in preclinical studies and clinical trials, and offer future perspectives. Fundamental research defining the mechanisms whereby PTMs of proteins regulate metabolic diseases will open new avenues for therapeutic intervention.

Role of Cyclic AMP in Cardiac β-Adrenoceptor Desensitization

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 09-1984

DOI: 10.1097/00005344-198409000-00009

Abstract: We examined the effects of prolonged exposure of cardiac cells in primary culture to the partial beta-adrenoceptor agonist prenalterol and inhibitors of phosphodiesterase on their subsequent ability to increase intracellular cyclic AMP during a 5-min exposure to 50 microM isoprenaline (receptor responsiveness). Although prenalterol possesses only 7% of the agonist activity of isoprenaline on adenylate cyclase, it induces extensive beta-adrenoceptor desensitization. Three hours after exposing the cells to 1 microM prenalterol, beta-adrenoceptor responsiveness was reduced by 40% (p less than 0.05), whereas after 12 h the reduction averaged 55%. Prolonging the incubation time to 48 h had no further effect on the magnitude of receptor desensitization. The magnitude of the desensitization was concentration dependent. On exposure of cells to 10(-8) M prenalterol for 16 h, receptor responsiveness was reduced by 19%, and at concentrations of 1 microM and higher responsiveness was reduced by 60% (p less than 0.01). Receptor desensitization appeared to be due to an inability of receptors to activate adenylate cyclase as well as to receptor loss. To investigate if beta-adrenoceptor desensitization as well as receptor loss could be mediated by cyclic AMP, the cells were exposed for 16 h to inhibitors of phosphodiesterase. Exposure of cells to the phosphodiesterase inhibitor isobutylmethylxanthine (0.1 mM) (which increased intracellular cyclic AMP by between 50 and 150%) also induced receptor desensitization. The reduction in receptor responsiveness averaged 62% (p less than 0.01). The loss in responsiveness could be accounted for by an inability of receptors to activate adenylate cyclase as well as by receptor loss.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycated and carboxy-methylated proteins do not directly activate human vascular smooth muscle cells

Publisher: Elsevier BV

Date: 12-2005

DOI: 10.1111/J.1523-1755.2005.00746.X

Abstract: Advanced glycation end products (AGEs) accumulate in patients with diabetes, particularly at sites of vascular damage and within atherosclerotic lesions, but whether they have direct actions on vascular smooth muscle cells (VSMCs) is controversial. AGEs were constructed and characterized by protein content, level of modification, fluorescence, and molecular size. Human VSMCs were derived from different vascular beds. Glucose consumption, de novo protein synthesis, and proteoglycan biosynthesis were measured using a colorimetric assay and metabolic radiolabeling. Receptor for AGEs (RAGE) expression was assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and Western blot. Treatment with AGEs under low or high glucose conditions showed no change in cellular glucose consumption or in cellular protein synthesis under low glucose conditions. Treatment of VSMCs with Nepsilon-(carboxymethyl)lysine in the presence of low glucose increased [35S]-sulfate incorporation into secreted proteoglycans by 72% (P < 0.001) and 67% (P < 0.001) however, the control proteins also increased [35S]-sulfate incorporation into proteoglycans by 56% (P < 0.01), with similar effects observed under high glucose conditions. Human VSMCs showed no difference in response to glycated and non-glycated protein. Protein and gene expression of RAGE in VSMC was approximately 50-fold lower compared to HMEC-1 and U937 cells, consistent with the immunohistochemical staining of RAGE in vivo. VSMCs show very low levels of RAGE expression thus, activation of VSMCs by AGEs does not occur. In diabetes, RAGE expression in VSM may increase to the extent that it becomes activated by AGEs in a manner that would contribute to the process of atherosclerosis.

1 Spontaneous Calcium Transients May Regulate Vascular Resistance

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 12-1987

DOI: 10.1097/00004872-198712000-00022

GPCR responses in vascular smooth muscle can occur predominantly through dual transactivation of kinase receptors and not classical Gαq protein signalling pathways

Publisher: Elsevier BV

Date: 05-2013

DOI: 10.1016/J.LFS.2013.03.017

Abstract: GPCR signalling is well known to proceed through several linear pathways involving activation of G proteins and their downstream signalling pathways such as activation of phospholipase C. In addition, GPCRs signal via transactivation of Protein Tyrosine Kinase receptors such as that for Epidermal Growth Factor (EGF) and Platelet-Derived Growth Factor (PDGF) where GPCR agonists mediate increase levels of phosphorylated Erk (pErk) the immediate downstream product of the activation of EGF receptor. It has recently been shown that this paradigm can be extended to include the GPCR transactivation of a Protein Serine/Threonine Kinase receptor, specifically the Transforming Growth Factor β Type I receptor (also known as Alk V) (TβRI) in which case GPCR activation leads to the formation of carboxy terminal polyphosphorylated Smad2 (phosphoSmad2) being the immediate downstream product of the activation of TβRI. Growth factor and hormone regulation of proteoglycan synthesis in vascular smooth muscle cells represent one component of an in vitro model of atherosclerosis because modified proteoglycans show enhanced binding to lipoproteins as the initiating step in atherosclerosis. In the ex le of proteoglycan synthesis stimulated by GPCR agonists such as thrombin and endothelin-1, the transactivation pathways for the EGF receptor and TβRI are both active and together account for essentially all of the response to the GPCRs. In contrast, signalling downstream of GPCRs such as increased inositol 1,4,5 trisphosphate (IP3) and intracellular calcium do not have any effect on GPCR stimulated proteoglycan synthesis. These data lead to the conclusion that dual transactivation pathways for protein tyrosine and serine/threonine kinase receptors may play a far greater role in GPCR signalling than currently recognised.

Intracellular pH in vascular smooth muscle: regulation by sodium-hydrogen exchange and multiple sodium dependent HCO3− mechanisms

Publisher: Oxford University Press (OUP)

Date: 02-1995

DOI: 10.1016/0008-6363(96)88576-2

Targeting epigenetics and non-coding RNAs in atherosclerosis: from mechanisms to therapeutics

Publisher: Elsevier BV

Date: 04-2019

DOI: 10.1016/J.PHARMTHERA.2018.11.003

Endothelin-1 Stimulation of Proteoglycan Synthesis in Vascular Smooth Muscle is Mediated by Endothelin Receptor Transactivation of the Transforming Growth Factor-β Type I Receptor

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 10-2010

DOI: 10.1097/FJC.0B013E3181EE6811

Gαq Is the Specific Mediator of PAR-1 Transactivation of Kinase Receptors in Vascular Smooth Muscle Cells.

Publisher: MDPI AG

Date: 20-11-2022

DOI: 10.3390/IJMS232214425

Abstract: Aims: G protein-coupled receptor (GPCR) transactivation of kinase receptors greatly expands the actions attributable to GPCRs. Thrombin, via its cognate GPCR, protease-activated receptor (PAR)-1, transactivates tyrosine and serine/threonine kinase receptors, specifically the epidermal growth factor receptor and transforming growth factor-β receptor, respectively. PAR-1 transactivation-dependent signalling leads to the modification of lipid-binding proteoglycans involved in the retention of lipids and the development of atherosclerosis. The mechanisms of GPCR transactivation of kinase receptors are distinct. We aimed to investigate the role of proximal G proteins in transactivation-dependent signalling. Main Methods: Using pharmacological and molecular approaches, we studied the role of the G⍺ subunits, G⍺q and G⍺11, in the context of PAR-1 transactivation-dependent signalling leading to proteoglycan modifications. Key Findings: Pan G⍺q subunit inhibitor UBO-QIC/FR900359 inhibited PAR-1 transactivation of kinase receptors and proteoglycans modification. The G⍺q/11 inhibitor YM254890 did not affect PAR-1 transactivation pathways. Molecular approaches revealed that of the two highly homogenous G⍺q members, G⍺q and G⍺11, only the G⍺q was involved in regulating PAR-1 mediated proteoglycan modification. Although G⍺q and G⍺11 share approximately 90% homology at the protein level, we show that the two isoforms exhibit different functional roles. Significance: Our findings may be extrapolated to other GPCRs involved in vascular pathology and highlight the need for novel pharmacological tools to assess the role of G proteins in GPCR signalling to expand the preeminent position of GPCRs in human therapeutics.

Therapeutic implications of endothelin and thrombin G-protein-coupled receptor transactivation of tyrosine and serine/threonine kinase cell surface receptors

Publisher: Oxford University Press (OUP)

Date: 20-08-2012

DOI: 10.1111/J.2042-7158.2012.01577.X

Abstract: This review discusses the latest developments in G protein coupled receptor (GPCR) signalling related to the transactivation of cell surface protein kinase receptors and the therapeutic implications. Multiple GPCRs have been known to transactivate protein tyrosine kinase receptors for almost two decades. More recently it has been discovered that GPCRs can also transactivate protein serine/threonine kinase receptors such as that for transforming growth factor (TGF)-β. Using the model of proteoglycan synthesis and glycosaminoglycan elongation in human vascular smooth muscle cells which is a component of an in vitro model of atherosclerosis, the dual tyrosine and serine/threonine kinase receptor transactivation pathways appear to account for all of the response to the agonists, endothelin and thrombin. The broadening of the paradigm of GPCR receptor transactivation explains the broad range of activities of these receptors and also the efficacy of GPCR antagonists in cardiovascular therapeutics. Deciphering the mechanisms of transactivation with the aim of identifying a common therapeutic target remains the next challenge.

Nerve growth factor protects retinal ganglion cells against injury induced by retinal ischemia–reperfusion in rats

Publisher: Informa UK Limited

Date: 24-02-2015

DOI: 10.3109/08977194.2015.1010642

Abstract: In this study, we investigated the protective effect of mouse nerve growth factor (NGF) on retinal ganglion cell (RGC) injury induced by retinal ischemia-reperfusion (RIR) in rats and explored its possible mechanisms of action. RIR caused a significant injury to RGCs and an obvious impairment of the inner retina functions, which could be seen from flash electroretinogram and flash visual evoked potential recordings. RIR also increased the expression of the apoptotic protein Bax while decreasing the expression of Bcl-2 and the phosphorylation of protein kinase B (Akt) in RGCs. Preinjection (i.m.) of NGF for 22 d reversed the injury induced by RIR and ameliorated the inner retina functions. NGF also reduced the expression of Bax and reversed the reduction of Bcl-2 and the phosphorylated Akt induced by RIR. These results indicate that NGF produces a neuroprotective effect on RGCs against RIR injury and the protective effect of NGF is mainly mediated by the PI-3K/Akt signaling pathway.

Endothelial Function and Dysfunction: Impact of metformin

Publisher: Elsevier BV

Date: 12-2018

DOI: 10.1016/J.PHARMTHERA.2018.07.007

Abstract: Cardiovascular and metabolic diseases remain the leading cause of morbidity and mortality worldwide. Endothelial dysfunction is a key player in the initiation and progression of cardiovascular and metabolic diseases. Current evidence suggests that the anti-diabetic drug metformin improves insulin resistance and protects against endothelial dysfunction in the vasculature. Hereby, we provide a timely review on the protective effects and molecular mechanisms of metformin in preventing endothelial dysfunction and cardiovascular and metabolic diseases.

Multidisciplinary involvement in completion of a hospital medication management plan in a tertiary hospital in australia

Publisher: Wiley

Date: 06-2016

DOI: 10.1002/JPPR.1146

Tu-P7:263 Vasoactive peptides stimulate atherogenic changes in vascular proteoglycans

Publisher: Elsevier BV

Date: 2006

DOI: 10.1016/S1567-5688(06)80966-9

Atherogenic, fibrotic and glucose utilising actions of glucokinase activators on vascular endothelium and smooth muscle

Publisher: Springer Science and Business Media LLC

Date: 15-04-2014

DOI: 10.1186/1475-2840-13-80

Forkhead family transcription factor FoxO and neural differentiation

Publisher: Springer Science and Business Media LLC

Date: 28-03-2012

DOI: 10.1007/S10048-012-0320-2

Abstract: The Forkhead Box subgroup O (FoxO) transcription factor family is one of the most important downstream targets of the phosphatidylinositol 3-kinase rotein kinase B signaling pathway playing an important role in many biological functions including transcriptional regulation of cellular differentiation. Neuronal differentiation is a complex process which involves many signaling pathways and molecular mechanisms. Interestingly, recent studies indicate that the FoxO family is involved in a number of signaling pathways regulating cell differentiation. The actions occur at different stages in the differentiation process and by differing mechanisms. This review will focus on FoxO as a novel transcription factor in neural differentiation.

Growth factor-mediated hyper-elongation of glycosaminoglycan chains on biglycan requires transcription and translation

Publisher: Informa UK Limited

Date: 07-2009

DOI: 10.1080/13813450903110754

Abstract: The mechanism through which growth factors cause glycosaminoglycan (GAG) hyper-elongation is unclear. We have investigated the role of transcription and translation on the GAG hyper-elongation effect of platelet-derived growth factor (PDGF) in human vascular smooth muscle cells (VSMCs). To determine if the response involves specific signalling pathways or the process of GAG hyper-elongation we have also investigated the effects of epidermal growth factor (EGF), transforming growth factor-beta (TGF-beta) and thrombin. We report that both actinomycin D and cycloheximide completely abolished the ability of PDGF to stimulate radiosulphate incorporation and GAG elongation into secreted proteoglycans, and to increase the size of xyloside GAGs. Blocking de novo protein synthesis completely prevented the action of all growth factors tested to elongate GAG chains. These results lay a foundation for further investigation into the genes and proteins implicated in this response.

Amiodarone-Induced Retinal Neuronal Cell Apoptosis Attenuated by IGF-1 via Counter Regulation of the PI3k/Akt/FoxO3a Pathway

Publisher: Springer Science and Business Media LLC

Date: 24-10-2016

DOI: 10.1007/S12035-016-0211-X

Abstract: Amiodarone (AM) is the most effective antiarrhythmic agent currently available. However, clinical application of AM is limited by its serious toxic adverse effects including optic neuropathy. The purpose of this study was to explore the effects of AM and to assess if insulin-like growth factor-1 (IGF-1) could protect retinal neuronal cells from AM-induced apoptosis, and to determine the molecular mechanisms underlying the effects. Accordingly, the phosphorylation/activation of Akt and FoxO3a were analyzed by Western blot while the possible pathways involved in the protection of IGF-1 were investigated by application of various pathway inhibitors. The full electroretinogram (FERG) was used to evaluate in vivo effect of AM and IGF-1 on rat retinal physiological functions. Our results showed that AM concentration dependently caused an apoptosis of RGC-5 cells, while IGF-1 protected RGC-5 cells against this effect by AM. The protective effect of IGF-1 was reversed by PI3K inhibitors LY294002 and wortmannin as well as the Akt inhibitor VIII. AM decreased p-Akt and p-FoxO3a while increased the nuclear localization of FoxO3a in the RGC-5 cells. IGF-1 reversed the effect of AM on the p-Akt and p-FoxO3a and the nuclear translocation of FoxO3a. Similar results were obtained in primary cultured retinal ganglia cells. Furthermore, FERG in vivo recording in rats showed that AM decreased a-wave and b-wave of FERG while IGF-1 reversed the effects of AM. These data show that AM induced apoptosis of retinal neuronal cells via inhibiting the PI3K/Akt/FoxO3a pathway while IGF-1 protected RGC-5 cells against AM-induced cell apoptosis by stimulating this pathway.

Effect of moderate alcohol upon obstructive sleep apnoea

Publisher: European Respiratory Society (ERS)

Date: 11-2000

DOI: 10.1183/09031936.00.16590900

Abstract: Moderate-to-large quantities of alcohol are known to aggravate severe obstructive sleep apnoea (OSA), however, the reported effects of moderate alcohol consumption upon mild-to-moderate OSA are inconsistent. Given the reported benefits of moderate alcohol consumption on cardiovascular mortality, recommendations regarding the management of patients with OSA are difficult to formulate. The aim of this study was to evaluate the effects of moderate alcohol on sleep and breathing in subjects with mild-to-moderate OSA. Twenty-one male volunteers, who snored habitually, underwent polysomnography with and without 0.5 g alcohol x kg body weight (BW)(-1) consumed 90 min prior to sleep time, in random order. The mean blood alcohol concentration (BAC) following alcohol at the time of lights out was 0.07 g x dL(-1). The distribution amongst the various sleep stages was not significantly altered by alcohol. The mean apnoea/hypopnoea index rose from 7.1+/-1.9 to 9.7+/-2.1 events x h(-1) (mean+/-SEM, p=0.017) however, there was no significant change in the minimum arterial oxygen saturation measured by pulse oximetry Sp,O2, apnoea length or snoring intensity. Mean sleep cardiac frequency rose significantly from 53.9+/-1.4 to 59.9+/-1.9 beats x min(-1) (P<0.001) and overnight urinary noradrenalin increased from 14.9+/-2.3 to 18.8+/-2.3 nmol x mmol creatinine(-1) (p=0.061) on the alcohol night compared to the nonalcohol night. To conclude, modest alcohol consumption, giving a mean blood alcohol concentration of 0.07 g x dL(-1), significantly increases both obstructive sleep apnoea frequency and mean sleep cardiac frequency.

Endothelin-1 and endothelin-3 stimulate calcium mobilization by different mechanisms in vascular smooth muscle

Publisher: Elsevier BV

Date: 03-1992

DOI: 10.1016/0006-291X(92)90538-V

Abstract: The mechanisms by which endothelin-1 (ET-1) and endothelin-3 (ET-3) stimulate Ca2+ mobilization were investigated in rat aortic smooth muscle cells. Both ET-1 and ET-3 potently stimulated mobilization of Ca2+ from intracellular stores, however only ET-1-stimulated Ca2+ mobilization appeared to occur as a consequence of an elevation in cellular inositol trisphosphate (IP3) concentration. Neomycin, an inhibitor of phospholipase C, inhibited both the increase in [3H]IP3 formation and the mobilization of Ca2+ induced by ET-1, however it did not affect Ca2+ mobilization induced by ET-3. Together these findings indicate that ET-1 stimulates Ca2+ mobilization via an increase in IP3, whereas the effect of ET-3 appears to be mediated by a separate, IP3-independent signalling pathway.

High glucose abolishes the antiproliferative effect of 17β-estradiol in human vascular smooth muscle cells

Publisher: American Physiological Society

Date: 04-2002

DOI: 10.1152/AJPENDO.00111.2001

Abstract: We examined effects of 17β-estradiol (E 2 ) on human vascular smooth muscle cell (VSMC) proliferation under normal (5 mmol/l) and high (25 mmol/l) glucose concentrations. Platelet-derived growth factor (PDGF) BB (20 ng/ml)-induced increases in DNA synthesis and proliferation were greater in high than normal glucose concentrations the difference in DNA synthesis was abolished by a protein kinase C (PKC)-β inhibitor, LY-379196 (30 nmol/l). Western blotting showed that PKC-β 1 protein increased in cells exposed to high glucose, whereas PKC-α protein and total PKC activity remained unchanged, compared with normal glucose cultures. In normal glucose, E 2 (1–100 nmol/l) inhibited PDGF-induced DNA synthesis by 18–37% and cell proliferation by 16–22% in a concentration-dependent manner. The effects of E 2 were blocked by the estrogen receptor (ER) antagonist ICI-182780, indicating ER dependence. In high glucose, the inhibitory effect of E 2 on VSMC proliferation was abolished but was restored in the presence of the PKC-β inhibitor LY-379196. Thus high glucose enhances human VSMC proliferation and attenuates the antiproliferative effect of E 2 in VSMC via activation of PKC-β.

Cellular and cytokine-based inflammatory processes as novel therapeutic targets for the prevention and treatment of atherosclerosis

Publisher: Elsevier BV

Date: 09-2011

DOI: 10.1016/J.PHARMTHERA.2011.04.001

Abstract: Cardiovascular disease is the largest cause of morbidity and premature mortality and its major underlying pathology is atherosclerosis. Atherosclerosis commences with the deposition of lipids in the artery wall due to trapping by proteoglycans. Trapped lipoproteins are chemically and enzymatically modified to yield pro-inflammatory species that induce adhesion molecule expression on endothelial cells leading to the recruitment of multiple species of immune cells and a chronic inflammatory response. Ongoing remodelling of the vessel and later morphological changes generate "vulnerable" plaques, the acute rupture of which generates the clinical event. The major medical therapies are anti-hypertensives and lipid lowering agents. Although these therapies are amongst the most efficacious in cardiovascular medicine, in optimised well-controlled clinical trials the maximum effect is limited to an approximately 30% reduction in cardiovascular events. Hence, a huge burden of disease remains refractory to current therapies and atherosclerosis and its sequelae persist as a therapeutic target of immense importance. Potential therapeutic targets include the proteoglycan: lipoprotein interaction in the vessel wall, circulating and vessel wall associated atherogenic lipid species and the immune system. Anti-inflammatory therapies include specific cytokine antagonists and cytokine neutralizing antibodies, specific immune cell depleting antibodies and cell therapies using antigen specific regulatory T-cells and regulatory B-cells. In this review, we describe the process of atherosclerosis as it involves the role of chronic inflammation in the development and progression of atherosclerotic plaques and then the manner in which some of these inflammatory processes represent therapeutic targets.

REGULATION OF SODIUM INFLUX AND SODIUM, POTASSIUM PUMP ACTIVITY BY A SODIUM‐HYDROGEN ANTIPORT IN RAT VASCULAR SMOOTH MUSCLE

Publisher: Wiley

Date: 03-1987

DOI: 10.1111/J.1440-1681.1987.TB00374.X

Abstract: 1. The effects of Na-H antiport inhibitors on sodium influx, intracellular pH and Na,K-pump activity were examined in vascular smooth muscle from rats. 2. Amiloride and 5-(N-ethyl-N-isopropyl)amiloride inhibited Na accumulation following inhibition of the Na,K-pump. 3. Inhibition of Na influx was associated with a reduction in basal Na,K-pump activity and intracellular pH. 4. It is concluded that a Na-H antiport system in vascular smooth muscle regulates Na influx rate, contributes to intracellular pH regulation and influences basal levels of Na,K-pump activity.

Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells

Publisher: Elsevier BV

Date: 05-2002

DOI: 10.1016/S0021-9150(01)00704-3

Abstract: The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.

Transforming growth factor–β1 mediated CHST11 and CHSY1 mRNA expression is ROS dependent in vascular smooth muscle cells

Publisher: Springer Science and Business Media LLC

Date: 11-11-2018

DOI: 10.1007/S12079-018-0495-X

3-Methylcholanthrene does not induce in vitro xenobiotic metabolism in spiny lobster hepatopancreas, or affect in vivo disposition of benzo[a]pyrene

Publisher: Elsevier BV

Date: 1984

DOI: 10.1016/0742-8413(84)90076-8

Abstract: Administration of 3-methylcholanthrene (10 mg/kg) i.m. to spiny lobsters, Panulirus argus, did not cause induction of the cytochrome P-450 content of hepatopancreas microsomes. The rate of oxidation of benzo[a]pyrene or 7-ethoxyresorufin in reductase-fortified preparations of hepatopancreas microsomes was the same for corn oil-treated or 3-methylcholanthrene-treated lobsters. Administration of 3-methylcholanthrene (10 mg/kg) i.m. to spiny lobsters one week prior to an i.v. dose of [14C]benzo[a]pyrene (1 mg/kg) did not influence the disposition of the radiolabelled benzo[a]pyrene in lobsters. At one week after the dose of [14C]benzo[a]pyrene, approximately 40% of the dose of [14C]benzo[a]pyrene remained in the lobsters, regardless of treatment. The digestive tract (hepatopancreas, intestinal contents, stomach and intestine) contained most (86%) of the 14C remaining in the lobsters.

Flow-dependent epigenetic regulation of IGFBP5 expression by H3K27me3 contributes to endothelial anti-inflammatory effects

Publisher: Ivyspring International Publisher

Date: 2018

DOI: 10.7150/THNO.21966

SODIUM‐DEPENDENT, ETHYLISOPROPYLAMILORIDE‐SENSITIVE MECHANISMS REGULATE INTRACELLULAR pH IN HUMAN VASCULAR SMOOTH MUSCLE

Publisher: Wiley

Date: 04-1990

DOI: 10.1111/J.1440-1681.1990.TB01324.X

Abstract: 1. The pH-sensitive dye 2,7-biscarboxy-ethyl-5(6)-carboxyfluorescein (BCECF) was used to examine the contribution of Na(+)-H+ exchange and bicarbonate-dependent processes to intracellular pH (pHi) regulation in cultured human vascular smooth muscle. 2. The recovery of pHi following an NH4Cl-induced acidosis was Na(+)-dependent and could be inhibited by ethylisopropylamiloride (200 mumols/L). Recovery was unaffected by the anion exchange inhibitor 4-acetamido-4'-isothio-cyano-stilbene-2,2'-disulfonic acid (200 mumols/L). 3. Recovery from intracellular acidosis was more rapid when bicarbonate ions were present in the extracellular medium. 4. The results suggest that Na(+)-H+ exchange as well as an Na(+)-dependent bicarbonate process, which can be inhibited by ethylisopropylamiloride, can influence the ability of smooth muscle to recover from intracellular acidosis.

Pyrido-Pyrimidine Derivative CYC10424 Inhibits Glycosaminoglycan Changes on Vascular Smooth Muscle-derived Proteoglycans and Reduces Lipoprotein Binding

Publisher: Ovid Technologies (Wolters Kluwer Health)

Date: 11-2008

DOI: 10.1097/FJC.0B013E31818A8907

Tanshinone IIA Attenuates Insulin Like Growth Factor 1 -Induced Cell Proliferation in PC12 Cells through the PI3K/Akt and MEK/ERK Pathways

Publisher: MDPI AG

Date: 12-09-2018

DOI: 10.3390/IJMS19092719

Abstract: The insulin like growth factor 1 (IGF-1) and its receptor (IGF-1R) facilitate tumor proliferation and progression. Tanshinone IIA (TSN) is an active diterpene quinone isolated from the roots of the herbal plant Salvia miltiorrhiza. TSN inhibits the proliferation of various types of cancer cells but its role in the IGF-1R-induced proliferation of pheochromocytoma (PC12) cells and the potential mechanisms are largely unknown. This study aims to investigate the anti-proliferative effect of TSN in PC12 cells and its role on IGF-1R signaling transduction. PC12 cells were treated with IGF-1 with or without TSN, methyl thiazolytetrazolium (MTT) assay, and cell counting kit-8 and flow cytometry were used to evaluate the proliferation of PC12 cells. The role of TSN on the apoptosis of PC12 cells were detected by flow cytometry as well. The effects of TSN and IGF-1 on the phosphorylation of IGF-1R, protein kinase B (Akt), extracellular-signal related kinase 1/2 (ERK1/2) and other downstream targets were analyzed by Western blotting analysis. Our results showed that IGF-1 promoted the growth of PC12 cells in a dose-dependent manner and increased the phosphorylation of IGF-1R, whereas TSN attenuated the effect of IGF-1. Interestingly, TSN did not induce cell apoptosis in PC12 cells. Moreover, TSN attenuated the phosphorylation of Akt and ERK1/2 induced by IGF-1, and the phosphorylation of glycogen synthase kinase-3β, forkhead box O3a (FOXO3a) and c-Raf were also inhibited by TSN. Furthermore, TSN inhibited cell growth induced by IGF-1 and blocked the activation of IGF-1R in SH-SY5Y cells. Taken together, TSN has an inhibitory effect on the proliferation of PC12 cells via down-regulation of the phosphorylated IGF-1R and its downstream signaling.

Transforming growth factor β-mediated site-specific Smad linker region phosphorylation in vascular endothelial cells

Publisher: Oxford University Press (OUP)

Date: 14-10-2014

DOI: 10.1111/JPHP.12298

Abstract: Transforming growth factor (TGF)-β regulates the function of vascular endothelial cells and may be involved in endothelial dysfunction. The canonical TGF-β pathway involves TGF-β receptor-mediated carboxy-terminal phosphorylation of Smad2 however, TGF-β signalling also activates numerous serine/threonine kinases that phosphorylate Smad2 in its linker region. The expression of phosphorylated Smad linker proteins were determined following TGF-β stimulation in the absence and presence of different serine/threonine kinase inhibitors in vascular endothelial cells. Proteins were quantified by Western blotting using specific antibodies to in idual phosphorylated Smad2 linker region residues. TGF-β mediated the phosphorylation of all four Smad2 linker region residues of interest. Erk and Jnk specifically phosphorylate Ser245 while all mitogen-activated protein kinases phosphorylate Ser250 and Ser255. Thr220 and Ser245 are phosphorylated by phosphoinositide 3 kinase (PI3K), while Ser255 was phosphorylated by the PI3K/Akt pathway. CDK and GSK-3 were shown to phosphorylate Thr220 and Ser245. TGF-β also mediated plasminogen activator inhibitor-1 gene expression that was attenuated by p38 and CDK inhibitors. TGF-β-mediated phosphorylation of in idual serine/threonine sites in the linker region of Smad2 occurs in a highly specific manner by kinases. These phosphorylations provide an opportunity to further understand a therapeutically targeted and very specific signalling pathway in vascular endothelial cells.

The role of specific Smad linker region phosphorylation in TGF-β mediated expression of glycosaminoglycan synthesizing enzymes in vascular smooth muscle

Publisher: Elsevier BV

Date: 08-2016

DOI: 10.1016/J.CELLSIG.2016.05.002

Abstract: Hyperelongation of glycosaminoglycan chains on proteoglycans facilitates increased lipoprotein binding in the blood vessel wall and the development of atherosclerosis. Increased mRNA expression of glycosaminoglycan chain synthesizing enzymes in vivo is associated with the development of atherosclerosis. In human vascular smooth muscle, transforming growth factor-β (TGF-β) regulates glycosaminoglycan chain hyperelongation via ERK and p38 as well as Smad2 linker region (Smad2L) phosphorylation. In this study, we identified the involvement of TGF-β receptor, intracellular serine/threonine kinases and specific residues on transcription factor Smad2L that regulate glycosaminoglycan synthesizing enzymes. Of six glycosaminoglycan synthesizing enzymes, xylosyltransferase-1, chondroitin sulfate synthase-1, and chondroitin sulfotransferase-1 were regulated by TGF-β. In addition ERK, p38, PI3K and CDK were found to differentially regulate mRNA expression of each enzyme. Four in idual residues in the TGF-β receptor mediator Smad2L can be phosphorylated by these kinases and in turn regulate the synthesis and activity of glycosaminoglycan synthesizing enzymes. Smad2L Thr220 was phosphorylated by CDKs and Smad2L Ser250 by ERK. p38 selectively signalled via Smad2L Ser245. Phosphorylation of Smad2L serine residues induced glycosaminoglycan synthesizing enzymes associated with glycosaminoglycan chain elongation. Phosphorylation of Smad2L Thr220 was associated with XT-1 enzyme regulation, a critical enzyme in chain initiation. These findings provide a deeper understanding of the complex signalling pathways that contribute to glycosaminoglycan chain modification that could be targeted using pharmacological agents to inhibit the development of atherosclerosis.

Fixed-dose statins with no lipid targets: a new paradigm of dosing?

Publisher: Wiley

Date: 03-2014

DOI: 10.1002/J.2055-2335.2014.TB00020.X

University Of Queensland

Location: Australia

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University Of The Sunshine Coast

Location: Australia

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Xinhua College Of Sun Yat Sen University

Location: China

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Linkage Infrastructure, Equipment And Facilities - Grant ID: LE190100106

Start Date: 03-2019

End Date: 12-2019

Amount: $334,425.00

Funder: Australian Research Council