ORCID Profile
0000-0001-7758-5252
Current Organisations
Victor Chang Cardiac Research Institute
,
University of Western Australia
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Research Topics
In Research Link Australia (RLA), "Research Topics" refer to ANZSRC FOR and SEO codes. These topics are either sourced from ANZSRC FOR and SEO codes listed in researchers' related grants or generated by a large language model (LLM) based on their publications.
Top 5 Research Topics
ANZSRC Field of Research (FoR)
Photonics and Electro-Optical Engineering (excl. Communications) | Cardiorespiratory Medicine and Haematology | Medical Physiology | Crop and Pasture Biochemistry and Physiology | Electrical and Electronic Engineering | Medical Physics | Systems Physiology | Biomedical Engineering not elsewhere classified | Cell Physiology | Cardiology (incl. Cardiovascular Diseases) | Systems Biology
ANZSRC Socio-Economic Objective (SEO)
Winter Grains and Oilseeds not elsewhere classified | Cardiovascular System and Diseases | Expanding Knowledge in the Physical Sciences | Nervous System and Disorders | Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified | Environment not elsewhere classified | Neurodegenerative Disorders Related to Ageing |
Related Links
Publications
Thyroid status and Na+-K+ pump current, intracellular sodium, and action potential duration in rabbit heart
Publisher: American Physiological Society
Date: 05-1995
DOI: 10.1152/AJPHEART.1995.268.5.H1838
Abstract: Thyroid status influences the abundance of Na(+)-K+ pumps in the heart. To evaluate whether this phenomenon may contribute to a dependence of the action potential duration (APD) on thyroid status, we induced hypothyroidism in a group of New Zealand White rabbits. Another group was treated similarly but also received triiodothyronine (T3). Right ventricular myocytes were isolated and voltage cl ed at -40 mV. We identified Na(+)-K+ pump current (Ipump) as a ouabain-induced shift in holding current. Mean Ipump, measured using patch pipettes containing 10 mM Na+, was 0.24 +/- 0.02 pA F in 9 cells from 4 hypothyroid rabbits and 0.48 +/- 0.05 in 10 cells from 4 rabbits treated with T3 (P 0.001). Because thyroid status influences Na+ influx, we measured intracellular Na+ activity (aiNa) in right ventricular papillary muscles. We found that aiNa was 5.20 +/- 0.42 mM in nine papillary muscles from seven hypothyroid rabbits and 7.62 +/- 0.69 mM in nine papillary muscles from six rabbits treated with T3 (P 0.01). The effect of thyroid-induced changes in Ipump and aiNa on APD was stimulated with a computer model. The simulations predicted that thyroid-induced changes in Ipump can influence APD. The predicted changes were similar to changes in APD measured in isolated papillary muscles.
The role of calcium and the L-type calcium channel in pathological remodeling of the heart
Publisher: Bentham Science Publishers Ltd.
Date: 05-2008
Elucidating the role of the L-type calcium channel in excitability and energetics in the heart
Publisher: Elsevier BV
Date: 11-2022
DOI: 10.1016/J.YJMCC.2022.08.001
Abstract: Cardiovascular disease continues to be the leading health burden worldwide and with the rising rates in obesity and type II diabetes and ongoing effects of long COVID, it is anticipated that the burden of cardiovascular morbidity and mortality will increase. Calcium is essential to cardiac excitation and contraction. The main route for Ca
The effect of acute hypoxia on excitability in the heart and the L-type calcium channel as a therapeutic target
Publisher: Bentham Science Publishers Ltd.
Date: 12-2008
DOI: 10.2174/157016308786733546
Abstract: Acute hypoxia is induced during coronary occlusion or when oxygen supply does not meet demand and can trigger cardiac arrhythmia. Cardiac ion channels shape the action potential and excitability of the heart. Acute hypoxia regulates the function of cardiac ion channels including the L-type Ca(2+) channel that is the main route for Ca(2+)influx into cardiac myocytes and shapes the plateau phase of the action potential. This article will review the evidence for alteration of ion channel function during hypoxia as a result of modification of thiol groups by reactive oxygen species. The effect of acute hypoxia on cardiac excitability will be examined and how this can lead to life threatening arrhythmias with particular reference to the L-type Ca(2+) channel. Recent evidence indicates the L-type Ca(2+) channel is a suitable target for the development of drugs that can modify channel function during hypoxia or oxidative stress to prevent induction of arrhythmia or development of pathology.
The Role of the Cysteine-Rich Domain and Netrin-Like Domain of Secreted Frizzled-Related Protein 4 in Angiogenesis Inhibition In Vitro
Publisher: Computers, Materials and Continua (Tech Science Press)
Date: 2012
DOI: 10.3727/096504012X13425470196010
Abstract: Secreted frizzled-related protein 4 (sFRP4) is a Wnt signaling antagonist. Classically, sFRP4 antagonizes the canonical Wnt signaling pathway, resulting in decreased cellular proliferation and increased apoptosis. Recent research from our laboratory has established that sFRP4 inhibits angiogenesis by decreasing proliferation, migration, and tube formation of endothelial cells. The objective of this study was to examine the role of sFRP4's cysteine-rich domain (CRD) and netrin-like domain (NLD) in angiogenesis inhibition. Experiments were carried out to examine cell death and tube formation of endothelial cells after treatment with the CRD and the NLD. The CRD was seen to inhibit tube formation of endothelial cells, which suggests that this domain is important to sFRP4's antiangiogenesis property. In addition, the NLD promoted endothelial cell death and may also inhibit angiogenesis. Furthermore, treatment with the CRD and the NLD increased endothelial intracellular calcium levels. Our findings implicate a role for both the CRD and NLD in angiogenesis inhibition by sFRP4. It is suggestive of alternative antiangiogenic downstream targets of canonical Wnt signaling and a possible importance of the noncanonical Ca2+ Wnt signaling pathway in sFRP4-mediated angiogenesis inhibition.
Arrhythmogenic Vulnerability is Associated with Alterations in Ion Channel Expression, Localization and Function in Hypertrophic Cardiomyopathy
Publisher: Elsevier BV
Date: 02-2020
AIGaN/GaN-based biosensor for label-free detection of biological activity
Publisher: Elsevier BV
Date: 02-2013
Evidence for redox sensing by a human cardiac calcium channel
Publisher: Springer Science and Business Media LLC
Date: 11-01-2016
DOI: 10.1038/SREP19067
Abstract: Ion channels are critical to life and respond rapidly to stimuli to evoke physiological responses. Calcium influx into heart muscle occurs through the ion conducting α1C subunit (Ca v 1.2) of the L-type Ca 2+ channel. Glutathionylation of Ca v 1.2 results in increased calcium influx and is evident in ischemic human heart. However controversy exists as to whether direct modification of Ca v 1.2 is responsible for altered function. We directly assessed the function of purified human Ca v 1.2 in proteoliposomes. Truncation of the C terminus and mutation of cysteines in the N terminal region and cytoplasmic loop III-IV linker did not alter the effects of thiol modifying agents on open probability of the channel. However mutation of cysteines in cytoplasmic loop I-II linker altered open probability and protein folding assessed by thermal shift assay. We find that C543 confers sensitivity of Ca v 1.2 to oxidative stress and is sufficient to modify channel function and posttranslational folding. Our data provide direct evidence for the calcium channel as a redox sensor that facilitates rapid physiological responses.
Can integrins integrate vascular myogenic responses?
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-03-2002
Intracluster light at the frontier: A2744
Publisher: American Astronomical Society
Date: 10-2014
Unravelling the mysteries of mitochondria in health and disease
Publisher: Wiley
Date: 07-2021
DOI: 10.1113/JP281833
A new methodology for assessment of the performance of heartbeat classification systems
Publisher: Springer Science and Business Media LLC
Date: 30-01-2008
Correlates of Academic Performance in Online Higher Education: A Systematic Review
Publisher: Frontiers Media SA
Date: 25-02-2022
DOI: 10.3389/FEDUC.2022.820567
Abstract: The existing steady and continual rise of online learning in higher education has been accelerated by COVID-19 and resulted in a move away from solely on-c us teaching. Prior to the pandemic, online education was providing higher education to students who were returning to study to up-skill, are employed full-time, caring for family members, living rurally or remotely and/or for whom otherwise face-to-face c us learning was not a preference or option. To understand how we can better support online students in their unique circumstances and create an optimal learning environment, we must understand the factors associated with academic achievement within an online setting. This systematic review involved a search of relevant databases published between January 2009 and May 2021 examining factors and constructs related to academic performance in online higher education settings. Across 34 papers, 23 (67.6%) explored factors and constructs related to student characteristics including cognitive and psychological, demographic, university enrolment, and prior academic performance. Twenty-one (61.8%) papers explored learning environment factors including engagement, student experience, course design, and instructor. Our overall synthesis of findings indicates that academic performance in online learning is most strongly associated with motivation (including self-efficacy), and self-regulation. We propose three main implications of our review for online learning stakeholders such as educators and designers. Firstly, we argue that the wellbeing of online learners is important to understand, and future research should explore its impact on students’ experience and success in online higher education. Secondly, we emphasise the importance of developing and designing online courses utilising relevant frameworks and evidence-based principles. Finally, we propose an approach to promoting improved student cognitive and psychosocial experiences (such as self-efficacy, self-regulation, and perceived support) could be achieved by creating and incorporating an online learning orientation module at the commencement of enrolment. Systematic Review Registration: (website), identifier (registration number).
Online exams: exploring student experience and integrity behaviours as we return to campus
Publisher: Australasian Society for Computers in Learning in Tertiary Education
Date: 18-11-2022
Abstract: On c us activity is resuming following two years of working and studying at home. Institutions are now faced with the opportunity and challenge of reconnecting students with an on c us environment while retaining the flexibility of online learning and assessment. During the pandemic there was a large uptake in the use of online remote exams combined with a variety of assessment security measures including proctoring tools designed to monitor student behaviour. Scholars and commentators alike have reported on positive and negative effects of these online assessment and security measures (Coghlan et al., 2021 Harwell, 2020 Selwyn et al., 2021 Stewart, 2020 White, 2020 Zhou, 2020). In particular, online proctoring technologies have been reported by some scholars to improve academic integrity behaviours (Dawson, 2020 Dendir & Maxwell, 2020 Dyer et al., 2020 Gudiño Paredes et al., 2021 Hylton et al., 2016) while others have reported less favourable results impacting the broader student experience. For ex le, online exams have been shown to impact student satisfaction with their online exam experience (Dawson, 2020 Gudiño Paredes et al., 2021 Harwell, 2020 Jaap et al., 2021) and academic performance (Dendir & Maxwell, 2020 Lee & Fanguy, 2022 Milone et al., 2017). As students return to c us, institutions are faced with the dilemma of deciding what online assessment practices should be retained, adapted, or discarded. This Pecha Kucha reports on a comparison of off c us and on c us student experiences of online exams and assessment security measures including online proctoring. This Pecha Kucha will report on one of Australia’s largest university-wide student exam experience surveys. Our large dataset comprising over 12,000 total responses will reveal preliminary findings of student experience during Semester 2 2021 where students mostly completed online exams remotely at home, compared to student experience during Semester 1 2022 where students mostly completed online exams on-c us. Overall, proctoring conditions between the two teaching periods are relatively comparable, with the major difference being that for the on-c us held exams in Semester 1 2022, students were required to check-in at a physical booth and receive a wristband with QR reader allowing them subsequently check-in to the exam room where they then used their own device to complete the online exam. This study offers unique student perspectives and has allowed us to understand the impact of the varied proctoring and exam conditions on student satisfaction and wellbeing, as well as on academic integrity attitudes such as temptation to cheat and self-reported cheating behaviours. In keeping with the conference ‘reconnect’ theme we focus on comparing the online exam experience of students who have returned to c us with the experience of students who sat an online exam remotely in a private setting. In particular, we explore their satisfaction, preference, perceived academic performance, as well as their motivations and behaviours in relation to (not)cheating. This Pecha Kucha offers actionable insights in relation to the implementation of online exams and online proctoring for student who are studying off c us, but also for those who are returning to c us.
Myoglobinopathy is an adult-onset autosomal dominant myopathy with characteristic sarcoplasmic inclusions
Publisher: Springer Science and Business Media LLC
Date: 27-03-2019
DOI: 10.1038/S41467-019-09111-2
Abstract: Myoglobin, encoded by MB , is a small cytoplasmic globular hemoprotein highly expressed in cardiac myocytes and oxidative skeletal myofibers. Myoglobin binds O 2, facilitates its intracellular transport and serves as a controller of nitric oxide and reactive oxygen species. Here, we identify a recurrent c.292C T (p.His98Tyr) substitution in MB in fourteen members of six European families suffering from an autosomal dominant progressive myopathy with highly characteristic sarcoplasmic inclusions in skeletal and cardiac muscle. Myoglobinopathy manifests in adulthood with proximal and axial weakness that progresses to involve distal muscles and causes respiratory and cardiac failure. Biochemical characterization reveals that the mutant myoglobin has altered O 2 binding, exhibits a faster heme dissociation rate and has a lower reduction potential compared to wild-type myoglobin. Preliminary studies show that mutant myoglobin may result in elevated superoxide levels at the cellular level. These data define a recognizable muscle disease associated with MB mutation.
Evidence for significance of serine 1487 in β-adrenergic regulation of Cav1.2 channel protein function in genetically engineered mice
Publisher: Elsevier BV
Date: 03-2020
Role of G proteins in α1 -adrenergic inhibition of the β- adrenergically activated chloride current in cardiac myocytes
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 05-1997
DOI: 10.1124/MOL.51.5.853
Abstract: alpha1-Adrenergic receptor stimulation can inhibit the Cl- current activated by beta-adrenergic receptor agonists in guinea-pig ventricular myocytes. We investigated the role of G proteins in mediating this type of alpha-adrenergic response. The combined alpha- and beta-adrenergic agonist norepinephrine (NE) activated the Cl- current with an EC50 value of 53 nM. Preincubation of myocytes with PTX decreased the EC50 value for NE activation of the Cl- current to 5.9 nM, and addition of the alpha1-adrenergic receptor antagonist prazosin did not cause any further change in sensitivity to NE. These results suggest that the alpha1-adrenergic inhibition of beta-adrenergic responses is mediated through a PTX-sensitive G protein. However, PTX pretreatment also increased the sensitivity of the Cl- current to the selective beta-adrenergic agonist isoproterenol (Iso), which indicates that the PTX treatment increases the sensitivity to beta-adrenergic stimulation alone and that this could account for the PTX-induced change in sensitivity to NE. Consistent with this idea, the selective alpha1-adrenergic receptor agonist methoxamine was still able to inhibit the Cl- current activated by Iso in PTX-treated myocytes. However, the sensitivity to methoxamine was significantly decreased. In control cells, the Cl- current activated by 30 nM Iso was inhibited by methoxamine with an EC50 value of 8.3 microM, but in PTX-treated cells, the EC50 value was 284 microM. The EC50 for methoxamine inhibition was similarly increased when the Cl- current was activated by 300 nM Iso. These data suggest that the effects of PTX on alpha1-adrenergic responses can actually be explained by changes in the sensitivity to beta-adrenergic stimulation. To verify the role for a G protein in mediating the inhibitory alpha1-adrenergic response, we examined the effect of methoxamine on the Cl- current activated in cells dialyzed with the nonhydrolyzable GTP analogue guanosine-5'-O-(3-thio)triphosphate. Pre-exposure to methoxamine resulted in an attenuated response upon subsequent exposure to Iso alone. We conclude that alpha1-adrenergic inhibition of beta-adrenergic responses is mediated by a G protein-dependent mechanism that appears to be PTX-insensitive.
Qo site of mitochondrial complex III is the source of increased superoxide after transient exposure to hydrogen peroxide
Publisher: Elsevier BV
Date: 11-2010
DOI: 10.1016/J.YJMCC.2010.07.015
Abstract: Transient exposure of cardiac myocytes to hydrogen peroxide (H(2)O(2)) results in further production of superoxide by the mitochondria as a result of increased influx of calcium through the L-type Ca(2+) channel and increased calcium uptake by the mitochondria. The response persists as a result of positive feedback on the channel and induces alterations in protein synthesis and cell size consistent with the development of myocyte hypertrophy. The aim of this study was to investigate the site of increased superoxide production within the mitochondria. Exposure of myocytes to 30 μM H(2)O(2) (5 min) then 10 U/mL catalase (5 min) increased dihydroethidium (DHE) signal by 58.7 ± 12.0% (n=4) compared to myocytes exposed to 0 μM H(2)O(2) for 5 min followed by 10 U/mL catalase (n=9). Complex I inhibitors DPI (n=5) and rotenone (n=7) attenuated the increase in DHE signal due to H(2)O(2). Complex III inhibitors myxothiazol (n=16) and stigmatellin (n=5) also attenuated the increase in DHE signal due to H(2)O(2). However, antimycin A (inhibitor of Q(i) site of complex III) had no effect. We "isolated" complex III in the intact cell by applying succinate in the patch pipette and exposing the cell to rotenone and antimycin A. Myxothiazol and TCA cycle inhibitors α-keto-β-methyl-n-valeric acid (KMV) and 4-hydroxynonenal (4-HNE) completely attenuated the increase in DHE signal. Direct activation of the L-type Ca(2+) channel by voltage-step mimicked the increase in DHE signal after transient exposure to H(2)O(2) (47.6 ± 17.8%, n=6) while intracellular application of catalase attenuated the increase in DHE signal due to H(2)O(2) (n=6). We propose that elevated superoxide production after transient exposure to H(2)O(2) occurs at the Q(o) superoxide generation site of complex III in cardiac myocytes and that an increase in TCA cycle activity plays a significant role in mediating the response.
Stress signaling and cellular proliferation reverse the effects of mitochondrial mistranslation
Publisher: EMBO
Date: 13-11-2019
Neuronal nitric oxide synthase regulation of calcium cycling in ventricular cardiomyocytes is independent of Cav1.2 channel modulation under basal conditions
Publisher: Springer Science and Business Media LLC
Date: 10-12-2020
DOI: 10.1007/S00424-019-02335-7
Abstract: Neuronal nitric oxide synthase (nNOS) is considered a regulator of Ca v 1.2 L-type Ca 2+ channels and downstream Ca 2+ cycling in the heart. The commonest view is that nitric oxide (NO), generated by nNOS activity in cardiomyocytes, reduces the currents through Ca v 1.2 channels. This gives rise to a diminished Ca 2+ release from the sarcoplasmic reticulum, and finally reduced contractility. Here, we report that nNOS inhibitor substances significantly increase intracellular Ca 2+ transients in ventricular cardiomyocytes derived from adult mouse and rat hearts. This is consistent with an inhibitory effect of nNOS/NO activity on Ca 2+ cycling and contractility. Whole cell currents through L-type Ca 2+ channels in rodent myocytes, on the other hand, were not substantially affected by the application of various NOS inhibitors, or application of a NO donor substance. Moreover, the presence of NO donors had no effect on the single-channel open probability of purified human Ca v 1.2 channel protein reconstituted in artificial liposomes. These results indicate that nNOS/NO activity does not directly modify Ca v 1.2 channel function. We conclude that—against the currently prevailing view—basal Ca v 1.2 channel activity in ventricular cardiomyocytes is not substantially regulated by nNOS activity and NO. Hence, nNOS/NO inhibition of Ca 2+ cycling and contractility occurs independently of direct regulation of Ca v 1.2 channels by NO.
Correction: Interrogating cardiac muscle cell mechanobiology on stiffness gradient hydrogels
Publisher: Royal Society of Chemistry (RSC)
Date: 2022
DOI: 10.1039/D2BM90083A
Abstract: Correction for ‘Interrogating cardiac muscle cell mechanobiology on stiffness gradient hydrogels’ by Ian L. Chin et al. , Biomater. Sci. , 2021, 9 , 6795–6806, 0.1039/D1BM01061A.
Volume adaptation of neonatal cardiomyocyte spheroids in 3D stiffness gradient GelMA
Publisher: Wiley
Date: 14-10-2023
DOI: 10.1002/JBM.A.37456
Abstract: Present understandings of cardiomyocyte mechanobiology have primarily been developed using 2‐dimensional, monocellular cell cultures, however the emergence of 3‐dimensional (3D) multicellular cardiac constructs has enabled us to develop more sophisticated recapitulations of the cardiac microenvironment. Several of these strategies have illustrated that incorporating elements of the extracellular matrix (ECM) can promote greater maturation and enhance desirable cardiac functions, such as contractility, but the responses of these cardiac constructs to biophysically aberrant conditions, such as in the post‐infarct heart, has remained relatively unexplored. In our study, we employ a stiffness gradient gelatin methacryloyl (GelMA) hydrogel platform to unpack the mechanobiology of cardiac spheroids. We encapsulated neonatal rat cardiac cell spheroids in a 4.4–18.7 kPa linear stiffness gradient up to 120 h. We found the proportion of viable cells within the spheroids increased over time, but the cell number per spheroid decreased. Spheroids expand more in softer matrices while stiffer matrices promote larger nuclei without changing nuclei shape. Volume expansion came primarily from cells expressing vimentin. We did not observe any correlations between stiffness and mechanomarker expression, however we found that after 120 h post‐encapsulation, the localization of YAP, the localization of MRTF‐A and the expression of Lamin‐A was correlated with spheroid morphology. The same trends were not observed 24 h post‐encapsulation, indicating that volume adaptation can take a relatively long time. Our data demonstrates that cardiac spheroids are mechanosensitive and that their capacity to respond to ECM‐based cues depends on their capacity to adapt their volume with a 3D microenvironment.
Real-Time Bioimpedance Sensing of Antifibrotic Drug Action in Primary Human Cells
Publisher: American Chemical Society (ACS)
Date: 19-09-2017
DOI: 10.1021/ACSSENSORS.7B00442
Abstract: Fibrotic diseases are among the most serious health issues with severe burdens due to their chronic nature and a large number of patients suffering from the debilitating effects and long-term sequelae. Collagenase treatment is a nonsurgical option but has limited results. To date, there is no potent noninvasive solution for fibrosis. Part of the reason for this is the lack of appropriate in vitro live cell screening tools to assess the efficacy of new therapeutical agents. Here, we demonstrate the utility of a cell-based electrochemical impedance biosensor platform to screen the efficacy of potential antifibrotic compounds. The platform employs a label-free and noninvasive strategy to detect the progression of fibrosis and the potency of the antifibrotic molecules in real-time. The fundamental principle that governs this novel system is that dynamic changes in cell shape and adhesion during fibrosis can be measured accurately by monitoring the changes in the impedance. This is achieved by growing the cells on a transparent interdigitated indium tin oxide (ITO) electrodes. It was demonstrated by monitoring the efficacy of a model antifibrotic compound, PXS64, on cells collected from patients with Dupuytren's contracture. We confirmed the validity of the developed biochemical impedance biosensor as an tool for in vitro screening of antifibrotic compounds and provided quantitative information on subcellular influences of the examined chemical molecules using correlative microscopy analyses that monitor the average cell area, cell morphology, and the amount and directionality of the deposited extracellular matrix protein collagen and measurement of cytosolic Ca
Impaired functional communication between the L-type calcium channel and mitochondria contributes to metabolic inhibition in the mdx heart
Publisher: Proceedings of the National Academy of Sciences
Date: 26-06-2014
Abstract: Duchenne muscular dystrophy (DMD) is a fatal X-linked disease that results in cardiomyopathy and heart failure. The cardiomyopathy is characterized by cytoskeletal protein disarray, contractile dysfunction, and reduced energy production. The mechanisms for altered energy metabolism are not yet fully clarified. The L-type Ca 2+ channel regulates excitation and contraction in the heart, and can regulate mitochondrial function via the movement of cytoskeletal proteins. Here, we find that myocytes from the murine model of DMD ( mdx ) exhibit impaired communication between the L-type Ca 2+ channel and the mitochondria that results in poor energy production. Morpholino oligomer therapy targeting dystrophin or block of the mitochondrial voltage-dependent anion channel (VDAC) “rescues” metabolic function, indicating that impaired communication between the L-type Ca 2+ channel and VDAC contributes to the cardiomyopathy.
Out of sight, but not out of mind: a case study of the collaborative development of a university-wide orientation resource for online students
Publisher: Springer Science and Business Media LLC
Date: 23-02-2022
DOI: 10.1007/S11423-022-10090-3
Abstract: The global online education sector has been rising rapidly, particularly during and after the events of 2020, and is becoming mainstream much sooner than expected. Despite this, research studies report higher levels of perceived isolation, difficulties with engagement, and higher attrition rates in online compared to equivalent on-c us programs. Reasons include restrictions to the type of institutional support accessible by online students, and the lack of comprehensiveness of orientation resources. This paper describes the collaborative efforts by a cross-faculty academic team, supported by a community of practice, to create a university-wide online orientation resource—the Monash Online Learning Hub (MOLH). The development of the MOLH involved multiple phases, including an analysis of current practice, resource design and content creation, formative evaluation by staff and students, and successful integration into the university’s mainstream student orientation platform for widescale implementation. The methods adopted were varied, and involved generating both qualitative and quantitative data across multiple phases of development from online education experts at the University, that culminated in the gradual building and refinement of the MOLH. Final outcomes, implications and lessons learned are also discussed in this paper.
A Morpholino Oligomer Therapy Regime That Restores Mitochondrial Function and Prevents mdx Cardiomyopathy
Publisher: Elsevier BV
Date: 06-2018
Mitochondrial mistranslation modulated by metabolic stress causes cardiovascular disease and reduced lifespan
Publisher: Wiley
Date: 07-06-2021
DOI: 10.1111/ACEL.13408
Abstract: Changes in the rate and fidelity of mitochondrial protein synthesis impact the metabolic and physiological roles of mitochondria. Here we explored how environmental stress in the form of a high‐fat diet modulates mitochondrial translation and affects lifespan in mutant mice with error‐prone ( Mrps12 ep / ep ) or hyper‐accurate ( Mrps12 ha / ha ) mitochondrial ribosomes. Intriguingly, although both mutations are metabolically beneficial in reducing body weight, decreasing circulating insulin and increasing glucose tolerance during a high‐fat diet, they manifest ergent (either deleterious or beneficial) outcomes in a tissue‐specific manner. In two distinct organs that are commonly affected by the metabolic disease, the heart and the liver, Mrps12 ep / ep mice were protected against heart defects but sensitive towards lipid accumulation in the liver, activating genes involved in steroid and amino acid metabolism. In contrast, enhanced translational accuracy in Mrps12 ha / ha mice protected the liver from a high‐fat diet through activation of liver proliferation programs, but enhanced the development of severe hypertrophic cardiomyopathy and led to reduced lifespan. These findings reflect the complex transcriptional and cell signalling responses that differ between post‐mitotic (heart) and highly proliferative (liver) tissues. We show trade‐offs between the rate and fidelity of mitochondrial protein synthesis dictate tissue‐specific outcomes due to commonly encountered stressful environmental conditions or aging.
Modelling Neuronal Activity Alterations Caused by MMW-THz Mediated Melting of Lipid Membrane
Publisher: IEEE
Date: 09-2018
Concerted regulation of mitochondrial and nuclear non-coding RNAs by a dual-targeted RNase Z
Publisher: EMBO
Date: 20-08-2018
Angiotensin-converting enzyme inhibitors regulate the Na+-K+ pump via effects on angiotensin metabolism
Publisher: American Physiological Society
Date: 07-1996
DOI: 10.1152/AJPCELL.1996.271.1.C172
Abstract: Treatment of rabbits with angiotensin-converting enzyme (ACE)-inhibiting drugs increases Na(+)-K+ pump current (Ip) of isolated cardiac myocytes when intracellular Na+ is at near-physiological levels. To examine if effects of ACE inhibitors are related to angiotensin metabolism, we measured Ip in myocytes isolated from rabbits treated with the AT1 receptor antagonist losartan. Ip was increased to levels similar to those after treatment with ACE inhibitors. Exposure of myocytes from captopril-treated rabbits to 10 nM angiotensin II (ANG II) for 45 min in vitro reduced Ip to levels similar to those of myocytes from untreated control rabbits. This rapid response to ANG II suggests that treatment with captopril had induced a functional change in preexisting pump units rather than synthesis of a new population of pumps. Consistent with this, we could not detect a change in Na(+)-K+ pump subunit mRNAs during treatment with captopril. The decrease in Ip of myocytes from captopril-treated rabbits induced by ANG II in vitro was blocked by pertussis toxin, bisindolylmaleimide I, and staurosporine. Exposure of myocytes to phorbol 12-myristate 13-acetate induced a decrease in Ip similar to that induced by ANG II. Thus ACE inhibitors regulate the Na(+)-K+ pump in myocytes via an effect on angiotensin metabolism. The regulatory mechanism appears to include the AT1 receptor, a G protein, and protein kinase C.
The L-type Ca2+channel as a therapeutic target in heart disease
Publisher: Bentham Science Publishers Ltd.
Date: 09-2009
DOI: 10.2174/092986709789057671
Abstract: The L-type Ca(2+) channel plays a critical role in cardiac function as the main route for entry of calcium into cardiac myocytes. It is essential to excitability as it shapes the long plateau phase of the cardiac action potential that is unique to cardiac ventricular myocytes. It is necessary for contraction as it triggers the release of calcium from sarcoplasmic reticulum stores for actin-myosin interaction. The L-type Ca(2+) channel also regulates cytoplasmic calcium levels. It is well recognised that an increase in intracellular calcium is involved in the activation of growth-promoting signal pathways. Recently reactive oxygen species have been implicated in the activation of signal pathways and the development of pathological hypertrophy. There is now evidence that implicates activation of the L-type Ca(2+) channel with persistent alterations in calcium homeostasis and cellular reactive oxygen species production as a possible trigger of cardiac hypertrophy. A number of different approaches have been used to modify channel function with the view to preventing ischemia-reperfusion injury, cardiac hypertrophy or cardiac failure providing good evidence that the L-type Ca(2+) channel may be an efficacious target in the prevention of cardiac pathology.
Lack of Strategic Funding and Long-Term Job Security Threaten to Have Profound Effects on Cardiovascular Researcher Retention in Australia
Publisher: Elsevier BV
Date: 11-2020
The interaction between electromagnetic fields at megahertz, gigahertz and terahertz frequencies with cells, tissues and organisms
Publisher: The Royal Society
Date: 12-2017
Abstract: Since regular radio broadcasts started in the 1920s, the exposure to human-made electromagnetic fields has steadily increased. These days we are not only exposed to radio waves but also other frequencies from a variety of sources, mainly from communication and security devices. Considering that nearly all biological systems interact with electromagnetic fields, understanding the affects is essential for safety and technological progress. This paper systematically reviews the role and effects of static and pulsed radio frequencies (10 0 –10 9 Hz), millimetre waves (MMWs) or gigahertz (10 9 –10 11 Hz), and terahertz (10 11 –10 13 Hz) on various biomolecules, cells and tissues. Electromagnetic fields have been shown to affect the activity in cell membranes (sodium versus potassium ion conductivities) and non-selective channels, transmembrane potentials and even the cell cycle. Particular attention is given to millimetre and terahertz radiation due to their increasing utilization and, hence, increasing human exposure. MMWs are known to alter active transport across cell membranes, and it has been reported that terahertz radiation may interfere with DNA and cause genomic instabilities. These and other phenomena are discussed along with the discrepancies and controversies from published studies.
Evidence of Altered Guinea Pig Ventricular Cardiomyocyte Protein Expression and Growth in Response to a 5 min in vitro Exposure to H2O2
Publisher: American Chemical Society (ACS)
Date: 26-02-2010
DOI: 10.1021/PR9011393
Abstract: Oxidative stress and alterations in cellular calcium homeostasis are associated with the development of cardiac hypertrophy. However, the early cellular mechanisms for the development of hypertrophy are not well understood. Guinea pig ventricular myocytes were exposed to 30 microM H(2)O(2) for 5 min followed by 10 units/mL catalase to degrade the H(2)O(2), and effects on protein expression were examined 48 h later. Transient exposure to H(2)O(2) increased the level of protein synthesis more than 2-fold, assessed as incorporation of [(3)H]leucine (n = 12 p < 0.05). Cell size was increased slightly, but there was no evidence of major cytoskeletal disorganization assessed using fluorescence microscopy. Changes in the expression of in idual proteins were assessed using iTRAQ protein labeling followed by mass spectrometry analysis (LC-MALDI-MSMS) 669 proteins were identified, and transient exposure of myocytes to H(2)O(2) altered expression of 35 proteins that were predominantly mitochondrial in origin, including TCA cycle enzymes and oxidative phosphorylation proteins. Consistent with changes in the expression of mitochondrial proteins, transient exposure of myocytes to H(2)O(2) increased the magnitude of the mitochondrial NADH signal 10.5 +/- 2.3% compared to cells exposed to 0 microM H(2)O(2) for 5 min followed by 10 units/mL catalase (n = 8 p < 0.05). In addition, metabolic activity was significantly increased in the myocytes 48 h after transient exposure to H(2)O(2), assessed as formation of formazan from tetrazolium salt. We conclude that a 5 min exposure of ventricular myocytes to 30 microM H(2)O(2) is sufficient to significantly alter protein expression, consistent with the development of hypertrophy in the myocytes. Changes in mitochondrial protein expression and function appear to be early sequelae in the development of hypertrophy.
An Evaluation of an Online Brief Mindfulness-Based Intervention in Higher Education: A Pilot Conducted at an Australian University and a British University
Publisher: Frontiers Media SA
Date: 28-10-2021
DOI: 10.3389/FPSYG.2021.752060
Abstract: Mental ill health among higher education students is a well-established problem therefore, it is imperative to implement preventative approaches to support wellbeing. Blended and fully online education programmes widens access for mature or returning students however, the psychological wellbeing of this sub-group of students is under-researched. Finally, evaluating wellbeing interventions that meet the needs of university students as well as accessible for online students is required. The aim of this study was to evaluate a brief, online and mindfulness-based intervention to assist the self-management of wellbeing and stress for both online and on-c us higher education students. The total s le included 427 participants (96% psychology students) at Monash University, Australia ( n =283) and King’s College London ( n =144), with 152 participants completing the whole study. Participants were allocated to a brief, self-guided, online and mindfulness-based intervention (over the course of one study period n =297), or to a wait-list control group ( n =148). Baseline and end of semester questionnaires included the 14-item Warwick-Edinburgh Mental Wellbeing Scale, 10-item Perceived Stress Scale and the 15-item Mindful Attention Awareness Scale. Regression modelling revealed the intervention condition accounted for up to 12% of the variability in change in student wellbeing, stress and mindfulness between the start and end of semester (when controlling for baseline). These findings support the implementation of a brief, online and asynchronous mindfulness-based intervention for supporting student mental health and psychological wellbeing. An on-going challenge in practice includes engaging and maintaining student engagement in wellbeing initiatives.
Secreted Frizzled-Related Protein 4. An Angiogenesis Inhibitor
Publisher: Elsevier BV
Date: 03-2010
Decreasing cellular hydrogen peroxide with catalase mimics the effects of hypoxia on the sensitivity of the L-type Ca 2+ channel to β-adrenergic receptor stimulation in cardiac myocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-10-2002
DOI: 10.1161/01.RES.0000035528.00678.D5
Abstract: In cardiac myocytes, hypoxia inhibits the basal L-type Ca 2+ current ( I Ca-L ) and increases the sensitivity of I Ca-L to β-adrenergic receptor stimulation. We investigated whether hydrogen peroxide (H 2 O 2 ) is involved in the hypoxic response. Guinea pig ventricular myocytes were dialyzed with catalase, which specifically catalyzes the conversion of H 2 O 2 to H 2 O and oxygen, and then I Ca-L was recorded during exposure to isoproterenol (Iso). Catalase decreased the K 0.5 for activation of I Ca-L by Iso from 2.7±0.3 nmol/L (in cells dialyzed with heat-inactivated catalase) to 0.4±0.1 nmol/L. The increase in sensitivity to Iso by catalase may be attenuated when cells are preexposed to H 2 O 2 . A significant increase in sensitivity of I Ca-L to Iso was recorded when mitochondrial function was inhibited with myxothiazol or FCCP, suggesting that the source of H 2 O 2 was from the mitochondria. Prior exposure of cells to H 2 O 2 attenuated the inhibition of basal I Ca-L during hypoxia and the increase in sensitivity of I Ca-L to Iso during hypoxia. Additionally, extracellularly applied catalase mimicked the effect of hypoxia on basal I Ca-L . Measurement of the rate of production of hydrogen peroxide using 5- (and 6-)chloromethyl-2′, 7′-dichlorodihydrofluorescein diacetate acetyl ester indicated that hypoxia was associated with a significant decrease in the production of hydrogen peroxide in the cells. These data suggest that hypoxia mediates changes in channel activity through a lowering in H 2 O 2 levels and that H 2 O 2 is a key intermediate in modifying basal channel activity and the β-adrenergic responsiveness of the channel during hypoxia.
Reactive oxygen species in cardiac signalling: From mitochondria to plasma membrane ion channels
Publisher: Wiley
Date: 2006
DOI: 10.1111/J.1440-1681.2006.04341.X
Abstract: 1. Reactive oxygen species (ROS) have been considered deleterious to cell function and there is good evidence to suggest that they play a role in the pathophysiology of a number of cardiac disease states. However, ROS are also now being recognized as important regulators of cell function by altering the redox state of proteins. 2. Possible sources of production of ROS in cardiac myocytes are the mitochondria and nicotinamide adenine dinucleotide phosphate-oxidase. The generation of ROS and anti-oxidant defence mechanisms in the heart are discussed. 3. The evidence for a role for ROS in the development of disease states, such as atherosclerosis, ischaemia, cardiac hypertrophy and hypertension, is presented. It is now recognized that cardiac ion channel function is regulated by ROS. Implications with respect to cardiac arrhythmia are discussed.
Characterization and validation of a preventative therapy for hypertrophic cardiomyopathy in a murine model of the disease
Publisher: Proceedings of the National Academy of Sciences
Date: 28-08-2020
Abstract: Hypertrophic cardiomyopathy affects 1:500 of the general population. Current drug therapy is used to manage symptoms in patients. There is an unmet need for treatments that can prevent the cardiomyopathy. Here we identify biomarkers of hypertrophic cardiomyopathy resulting from causing cardiac troponin I mutation Gly203Ser, and present a safe, nontoxic, preventative approach for the treatment of associated cardiomyopathy.
Glutathionylation of the L-type Ca2+channel in oxidative stress-induced pathology of the heart
Publisher: MDPI AG
Date: 22-10-2014
Characterising the Phenotypic Switch in a Murine Model of Hypertrophic Cardiomyopathy
Publisher: Elsevier BV
Date: 2020
Age and metallicity gradients support hierarchical formation for M87
Publisher: Oxford University Press (OUP)
Date: 05-02-2014
DOI: 10.1093/MNRAS/STU037
Changes in oxygen tension affect cardiac mitochondrial respiration rate via changes in the rate of mitochondrial hydrogen peroxide production
Publisher: Elsevier BV
Date: 07-2009
DOI: 10.1016/J.YJMCC.2009.03.010
Abstract: The capacity of mitochondria to respond to changes in oxygen delivery has the potential to affect the ability of the heart to tolerate decreased oxygen delivery. Respiration by mitochondria is typically regarded as independent of oxygen tension (pO(2)) until critically low oxygen concentrations limit the activity of cytochrome oxidase. Paradoxically, there is evidence that cellular and mitochondrial oxygen consumption (respiration) can decline at oxygen tensions well above this critical pO(2). We tested the hypothesis that oxygen sensitive decreases in mitochondrial hydrogen peroxide production can decrease cardiac mitochondrial respiration rate. Consistent with previous work, an acute decline in pO(2) from 146 mm Hg to 10-13 mm Hg in less than 10 min did not affect mitochondrial respiration rate. In contrast, sustained incubation of mitochondria at a pO(2) of 10-13 mm Hg for 30 min caused a 50% decrease in mitochondrial respiration rate. This decrease in mitochondrial respiration rate was mimicked by incubation with the hydrogen peroxide scavenger catalase and the decrease in mitochondrial respiration rate was fully reversible by reintroducing oxygen or by adding hydrogen peroxide. Incubation at low pO(2) was also associated with a decreased rate of mitochondrial reactive oxygen species production. These findings indicate that oxygen-dependent decreases in the rate of mitochondrial hydrogen peroxide production can decrease cardiac mitochondrial respiration.
Factors associated with online examination cheating
Publisher: Informa UK Limited
Date: 11-11-2023
Evidence for regulation of mitochondrial function by the L-type Ca2+ channel in ventricular myocytes
Publisher: Elsevier BV
Date: 06-2009
DOI: 10.1016/J.YJMCC.2008.12.015
Abstract: The L-type Ca(2+) channel is responsible for initiating contraction in the heart. Mitochondria are responsible for meeting the cellular energy demands and calcium is required for the activity of metabolic intermediates. We examined whether activation of the L-type Ca(2+) channel alone is sufficient to alter mitochondrial function. The channel was activated directly with the dihydropyridine agonist BayK(-) or voltage-cl of the plasma membrane and indirectly by depolarization of the membrane with high KCl. Activation of the channel increased superoxide production (assessed as changes in dihydroethidium fluorescence), NADH production and metabolic activity (assessed as formation of formazan from tetrazolium) in a calcium-dependent manner. Activation of the channel also increased mitochondrial membrane potential assessed as changes in JC-1 fluorescence. The response was reversible upon inactivation of the channel during voltage-cl of the plasma membrane and did not appear to require calcium. We examined whether the response may be mediated through movement of cytoskeletal proteins. Depolymerization of actin or exposing cells to a peptide directed against the alpha-interacting domain of the alpha(1C)-subunit of the channel (thereby preventing movement of the beta-subunit) attenuated the increase in mitochondrial membrane potential. We conclude that activation of the L-type Ca(2+) channel can regulate mitochondrial function and the response appears to be modulated by movement through the cytoskeleton.
Cav1.2 calcium channel is glutathionylated during oxidative stress in guinea pig and ischemic human heart
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1016/J.FREERADBIOMED.2011.07.005
Abstract: Glutathionylation as a posttranslational modification of proteins is becoming increasingly recognized, but its role in many diseases has not been demonstrated. Oxidative stress and alterations in calcium homeostasis are associated with the development of cardiac hypertrophy. Because the cardiac L-type Ca(2+) channel can be persistently activated after exposure to H(2)O(2), the aim of this study was to determine whether alterations in channel function were associated with glutathionylation of the α(1C) subunit (Ca(v)1.2) channel protein. Immunoblot analysis indicated that Ca(v)1.2 protein is significantly glutathionylated after exposure to H(2)O(2) and glutathione in vitro and after ischemia-reperfusion injury. L-type Ca(2+) channel macroscopic current and intracellular calcium were significantly increased in myocytes after exposure to oxidized glutathione and reversed by glutaredoxin. The increase in current correlated with an increase in open probability of the channel assessed as changes in single-channel activity after exposing the human long N-terminal Ca(v)1.2 to H(2)O(2) or oxidized glutathione. We also demonstrate that the Ca(v)1.2 channel is significantly glutathionylated in ischemic human heart. We conclude that oxidative stress is associated with an increase in glutathionylation of the Ca(v)1.2 channel protein. We suggest that the associated constitutive activity contributes to the development of pathology in ischemic heart disease.
Choline kinase β mutant mice exhibit reduced phosphocholine, elevated osteoclast activity, and low bone mass
Publisher: Elsevier BV
Date: 2015
Evidence for the regulation of L-type Ca2+ channels in the heart by reactive oxygen species: Mechanism for mediating pathology
Publisher: Wiley
Date: 15-08-2008
DOI: 10.1111/J.1440-1681.2007.04727.X
Abstract: 1. It is well recognized that reactive oxygen species (ROS) can activate transduction pathways to mediate pathophysiology. An increase in ROS has been implicated in a number of cardiovascular disorders. Reactive oxygen species regulate cell function through redox modification of target proteins. One of these target proteins is the L-type Ca(2+) channel. 2. There is good evidence that thiol reducing and oxidizing compounds, including hydrogen peroxide, can influence calcium channel function. The evidence for regulation of the channel protein and regulatory proteins by thiol-specific modifying agents and relevance to hypoxia and oxidative stress is presented. 3. Clinical studies suggest that calcium channel antagonists may be beneficial in reducing myocardial injury associated with oxidative stress. The identification of cysteines as possible targets for intervention during hypoxic trigger of arrhythmia or chronic pathological remodelling is discussed.
How cytoskeletal proteins regulate mitochondrial energetics in cell physiology and diseases
Publisher: The Royal Society
Date: 03-10-2022
Abstract: Mitochondria are ubiquitous organelles that play a pivotal role in the supply of energy through the production of adenosine triphosphate in all eukaryotic cells. The importance of mitochondria in cells is demonstrated in the poor survival outcomes observed in patients with defects in mitochondrial gene or RNA expression. Studies have identified that mitochondria are influenced by the cell's cytoskeletal environment. This is evident in pathological conditions such as cardiomyopathy where the cytoskeleton is in disarray and leads to alterations in mitochondrial oxygen consumption and electron transport. In cancer, reorganization of the actin cytoskeleton is critical for trans-differentiation of epithelial-like cells into motile mesenchymal-like cells that promotes cancer progression. The cytoskeleton is critical to the shape and elongation of neurons, facilitating communication during development and nerve signalling. Although it is recognized that cytoskeletal proteins physically tether mitochondria, it is not well understood how cytoskeletal proteins alter mitochondrial function. Since end-stage disease frequently involves poor energy production, understanding the role of the cytoskeleton in the progression of chronic pathology may enable the development of therapeutics to improve energy production and consumption and slow disease progression. This article is part of the theme issue ‘The cardiomyocyte: new revelations on the interplay between architecture and function in growth, health, and disease’.
Cross-talk between L-type Ca2+ channels and mitochondria
Publisher: Wiley
Date: 19-01-2010
DOI: 10.1111/J.1440-1681.2009.05277.X
Abstract: 1. Calcium is necessary for myocardial function, including contraction and maintenance of cardiac output. Calcium is also necessary for myocardial energetics and production of ATP by mitochondria, but the mechanisms for calcium regulation by mitochondria are still not fully resolved. 2. The cytoskeleton plays an important role in maintaining a cell's integrity. It is now recognized that cytoskeletal proteins can also assist in the transmission of signals from the plasma membrane to intracellular organelles. Cytoskeletal proteins can regulate the function of the L-type Ca(2+) channel and alter intracellular calcium homeostasis. 3. Recent evidence suggests that calcium influx through the L-type Ca(2+) channel is sufficient to alter a number of mitochondrial functional parameters, including superoxide production, NADH production and metabolic activity, assessed as the formation of formazan from tetrazolium salt. This occurs in a calcium-dependent manner. 4. Activation of the L-type Ca(2+) channel also alters mitochondrial membrane potential in a calcium-independent manner and this is assisted by movement of the auxiliary beta(2)-subunit through F-actin filaments. 5. Because the L-type Ca(2+) channel is the initiator of contraction, a functional coupling between the channels and mitochondria may assist in meeting myocardial energy demand on a beat-to-beat basis.
Intracluster light at the Frontier - II. The Frontier Fields clusters
Publisher: Oxford University Press (OUP)
Date: 02-11-2018
Redox control of calcium channels: From mechanisms to therapeutic opportunities
Publisher: Mary Ann Liebert Inc
Date: 04-2007
Abstract: Calcium plays an integral role in cellular function. It is a well-recognized second messenger necessary for signaling cellular responses, but in excessive amounts can be deleterious to function, causing cell death. The main route by which calcium enters the cytoplasm is either from the extracellular compartment or internal addistores via calcium channels. There is good evidence that calcium channels can respond to pharmacological compounds that reduce or oxidize thiol groups on the channel protein. In addition, reactive oxygen species such as hydrogen peroxide and superoxide that can mediate oxidative pathology also mediate changes in channel function via alterations of thiol groups. This review looks at the structure and function of calcium channels, the evidence that changes in cellular redox state mediate changes in channel function, and the role of redox modification of channels in disease processes. Understanding how redox modification of the channel protein alters channel structure and function is providing leads for the design of therapeutic interventions that target oxidative stress responses.
Protein kinase C isozyme selective peptides - a current view of what they tell us about location and function of isozymes in the heart
Publisher: Bentham Science Publishers Ltd.
Date: 02-2005
Abstract: The identification of protein kinase C isozymes in distinct localities within the cell has led to the suggestion that each isozyme mediates a unique function. This has necessitated the development of methodologies that are capable of assigning specific function to an isozyme. For many years the location of in idual isozymes in a particulate fraction was used to correlate specific isozymes with cellular function. More recently over-expression of selective isozymes and genetic knockouts have provided tissue-specific and developmentally regulated information on function. It is now known that specific proteins act as isozyme selective receptors for activated C kinase (RACKs) which determine subcellular localization of specific isozymes. As a result, peptides have been designed from the interaction site between the isozyme and its RACK that prevent the binding of isozymes to their respective RACKs. This has allowed the modulation of function of in idual isozymes. This review will examine the development of the peptides as isozyme selective inhibitors or activators of PKC and its impact on understanding the role of isozymes in cellular function in the healthy and diseased heart. The possible development of isozyme-specific drugs for therapeutic use will be discussed.
L-type calcium channel
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1016/J.BIOCEL.2017.03.010
Abstract: The heart is able to respond acutely to changes in oxygen tension. Since ion channels can respond rapidly to stimuli, the "ion channel oxygen sensing hypothesis" has been proposed to explain acute adaptation of cells to changes in oxygen demand. However the exact mechanism for oxygen sensing continues to be debated. Mitochondria consume the lion's share of oxygen in the heart, fuelling the production of ATP that drives excitation and contraction. Mitochondria also produce reactive oxygen species that are capable of altering the redox state of proteins. The cardiac L-type calcium channel is responsible for maintaining excitation and contraction. Recently, the reactive cysteine on the cardiac L-type calcium channel was identified. These data clarified that the channel does not respond directly to changes in oxygen tension, but rather responds to cellular redox state. This leads to acute alterations in cell signalling responsible for the development of arrhythmias and pathology.
Examining efficacy of tAT-less delivery of a peptide against the L-type calcium channel in cardiac ischemia-reperfusion injury
Publisher: American Chemical Society (ACS)
Date: 05-03-2013
DOI: 10.1021/NN305211F
Abstract: Increased calcium influx through the L-type Ca(2+) channel or overexpression of the alpha subunit of the channel induces cardiac hypertrophy. Cardiac hypertrophy results from increased oxidative stress and alterations in cell calcium levels following ischemia-reperfusion injury and is an independent risk factor for increased morbidity and mortality. We find that decreasing the movement of the auxiliary beta subunit with a peptide derived against the alpha-interacting domain (AID) of the channel attenuates ischemia-reperfusion injury. We compared the efficacy of delivering the AID peptide using a trans-activator of transcription (TAT) sequence with that of the peptide complexed to multifunctional polymeric nanoparticles. The AID-tethered nanoparticles perfused through the myocardium more diffusely and associated with cardiac myocytes more rapidly than the TAT-labeled peptide but had similar effects on intracellular calcium levels. The AID-complexed nanoparticles resulted in a similar reduction in release of creatine kinase and lactate dehydrogenase after ischemia-reperfusion to the TAT-labeled peptide. Since nanoparticle delivery also holds the potential for dual drug delivery, we conclude that AID-complexed nanoparticles may provide an effective platform for peptide delivery in cardiac ischemia-reperfusion injuries.
A platform for discovery of functional cell-penetrating peptides for efficient multi-cargo intracellular delivery
Publisher: Springer Science and Business Media LLC
Date: 22-08-2018
DOI: 10.1038/S41598-018-30790-2
Abstract: Cell penetrating peptides (CPPs) offer great potential to deliver therapeutic molecules to previously inaccessible intracellular targets. However, many CPPs are inefficient and often leave their attached cargo stranded in the cell’s endosome. We report a versatile platform for the isolation of peptides delivering a wide range of cargos into the cytoplasm of cells. We used this screening platform to identify multiple “Phylomer” CPPs, derived from bacterial and viral genomes. These peptides are amenable to conventional sequence optimization and engineering approaches for cell targeting and half-life extension. We demonstrate potent, functional delivery of protein, peptide, and nucleic acid analog cargos into cells using Phylomer CPPs. We validate in vivo activity in the cytoplasm, through successful transport of an oligonucleotide therapeutic fused to a Phylomer CPP in a disease model for Duchenne’s muscular dystrophy. This report thus establishes a discovery platform for identifying novel, functional CPPs to expand the delivery landscape of druggable intracellular targets for biological therapeutics.
How Does Calcium Regulate Mitochondrial Energetics in the Heart? - New Insights
Publisher: Elsevier BV
Date: 07-2014
DOI: 10.1016/J.HLC.2014.02.009
Abstract: Maintenance of cellular calcium homeostasis is critical to regulating mitochondrial ATP production and cardiac contraction. The ion channel known as the L-type calcium channel is the main route for calcium entry into cardiac myocytes. The channel associates with cytoskeletal proteins that assist with the communication of signals from the plasma membrane to intracellular organelles, including mitochondria. This article explores the roles of calcium and the cytoskeleton in regulation of mitochondrial function in response to alterations in L-type calcium channel activity. Direct activation of the L-type calcium channel results in an increase in intracellular calcium and increased mitochondrial calcium uptake. As a result, mitochondrial NADH production, oxygen consumption and reactive oxygen species production increase. In addition the L-type calcium channel is able to regulate mitochondrial membrane potential via cytoskeletal proteins when conformational changes in the channel occur during activation and inactivation. Since the L-type calcium channel is the initiator of contraction, a functional coupling between the channel and mitochondria via the cytoskeleton may represent a synchronised process by which mitochondrial function is regulated in addition to calcium influx to meet myocardial energy demand on a beat to beat basis.
Specific combinations of ion channel inhibitors reduce excessive Ca2+influx as a consequence of oxidative stress and increase neuronal and glial cell viability in vitro
Publisher: Elsevier BV
Date: 12-2016
DOI: 10.1016/J.NEUROSCIENCE.2016.10.005
Abstract: Combinations of Ca
Decreased myocardial injury and improved contractility after administration of a peptide derived against the alpha-interacting domain of the L-type calcium channel
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 22-05-2014
Abstract: Myocardial infarction remains the leading cause of morbidity and mortality associated with coronary artery disease. The L‐type calcium channel ( I C a‐L ) is critical to excitation and contraction. Activation of the channel also alters mitochondrial function. Here, we investigated whether application of a alpha‐interacting domain/transactivator of transcription ( AID ‐ TAT) peptide, which immobilizes the auxiliary β 2 subunit of the channel and decreases metabolic demand, could alter mitochondrial function and myocardial injury. Treatment with AID ‐ TAT peptide decreased ischemia‐reperfusion injury in guinea‐pig hearts ex vivo (n=11) and in rats in vivo (n=9) assessed with uptake of nitroblue tetrazolium, release of creatine kinase, and lactate dehydrogenase. Contractility (assessed with catheterization of the left ventricle) was improved after application of AID ‐ TAT peptide in hearts ex vivo (n=6) and in vivo (n=8) up to 12 weeks before sacrifice. In search of the mechanism for the effect, we found that intracellular calcium ([Ca 2+ ] i , Fura‐2), superoxide production (dihydroethidium fluorescence), mitochondrial membrane potential (Ψ m , JC ‐1 fluorescence), reduced nicotinamide adenine dinucleotide production, and flavoprotein oxidation (autofluorescence) are decreased after application of AID ‐ TAT peptide. Application of AID ‐ TAT peptide significantly decreased infarct size and supported contractility up to 12 weeks postcoronary artery occlusion as a result of a decrease in metabolic demand during reperfusion.
Bone marrow stromal cells as replacement cells for Parkinson's disease: Generation of an anatomical but not functional neuronal phenotype
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.TRSL.2010.11.001
Abstract: The focus of cell replacement therapies (CRTs) for Parkinson's disease has been on delivering dopamine-producing cells to the striatum. Fetal grafts have proven the feasibility of this approach, but an appropriate source of replacement cells has restricted the clinical translation. Bone marrow stromal cells (BMSCs) have been heralded as an ideal source of dopaminergic (DAergic) replacement cells, as they are viewed as ethically acceptable, easily procured, and readily expanded. It is known that they confer functional benefits, particularly in stroke models, through the release of neurotrophic factors, but their transdifferentiation into neurons is still under contention. We sought to evaluate the neuronal phenotype and functional capacity of adult rat BMSCs after exposure to a novel multistep in vitro differentiation protocol compared with cells exposed to other reported neuronal differentiation conditions. We employed a systematic, comprehensive method of assessment to determine the neuronal differentiation capacity of BMSCs. Our fluorescence-activated cell sorting, immunofluorescent and semiquantitative polymerase chain reaction results confirmed that undifferentiated BMSCs isolated based on their adherence to plastic are of mesenchymal origin and express a range of lineage markers. After exposure to preinduction and neuronal induction steps, BMSCs down-regulate markers of other lineages but fail, as assessed by patch cl , to differentiate into functional neurons. Thus, for BMSCs to be considered a source of DAergic neuronal replacement cells, their ability to transdifferentiate terminally along a neuronal lineage first must be clarified before attempting to direct more complex specification process required for them to be used in Parkinson's-disease-focused CRTs.
The L-type Ca2+channel facilitates abnormal metabolic activity in the cTnI-G203S mouse model of hypertrophic cardiomyopathy
Publisher: Wiley
Date: 12-06-2016
DOI: 10.1113/JP271681
Mechanosensitive channel of large conductance
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.BIOCEL.2007.02.003
Abstract: Microbial cells constitutively express the Large Conductance Mechanosensitive Channel which opens in response to stretch forces in the lipid bilayer. The channel protein forms a homopentamer with each subunit containing two transmembrane regions and gates via the bilayer mechanism evoked by hydrophobic mismatch and changes in the membrane curvature and/or transbilayer pressure profile. During the stationary phase and during osmotic shock the channel protein is up-regulated to prevent cell lysis. Pharmacological potential of MscL may involve discovery of new age antibiotics to combat multiple drug-resistant bacterial strains.
Fidelity of translation initiation is required for coordinated respiratory complex assembly
Publisher: American Association for the Advancement of Science (AAAS)
Date: 06-12-2019
Abstract: The initiation of mitochondrial protein synthesis fine-tunes the assembly of respiratory complexes and energy production.
Undressing M87 by exposing its most private globulars
Publisher: Cambridge University Press (CUP)
Date: 08-2012
DOI: 10.1017/S1743921313005206
Abstract: We present a multiwavelength photometric analysis of the innermost (3×3 kpc 2 ) Globular Clusters (GCs) of M87. Their Spectral Energy Distributions (SEDs) were built with J and K s imaging obtained with NaCo at the VLT, along with HST UV-optical archival data. Using both Galatic GC templates and stellar population models, we derived ages ( 10 Gyr) and metallicities ([Fe/H]~ −0.7) for these clusters (e.g: Cohen et al . 1998). These GCs have lower metallicities than its host galaxy. This agrees with the idea that the GC population formed earlier than the bulk of the stars.
Differences and Similarities between Millimetre Wave and Thermal Heating Effect on Action Potential Triggering in Leech Interneuron
Publisher: IEEE
Date: 09-2019
The potential for nanotechnology to improve delivery of therapy to the acute ischemic heart
Publisher: Future Medicine Ltd
Date: 04-2016
DOI: 10.2217/NNM.16.7
Abstract: Treatment of acute cardiac ischemia remains an area in which there are opportunities for therapeutic improvement. Despite significant advances, many patients still progress to cardiac hypertrophy and heart failure. Timely reperfusion is critical in rescuing vulnerable ischemic tissue and is directly related to patient outcome, but reperfusion of the ischemic myocardium also contributes to damage. Overproduction of reactive oxygen species, initiation of an inflammatory response and deregulation of calcium homeostasis all contribute to injury, and difficulties in delivering a sufficient quantity of drug to the affected tissue in a controlled manner is a limitation of current therapies. Nanotechnology may offer significant improvements in this respect. Here, we review recent ex les of how nanoparticles can be used to improve delivery to the ischemic myocardium, and suggest some approaches that may lead to improved therapies for acute cardiac ischemia.
Setting priorities for health education research: A mixed methods study
Publisher: Informa UK Limited
Date: 29-05-2019
Regulator of G-protein signaling 5 controls blood pressure homeostasis and vessel wall remodeling
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2013
DOI: 10.1161/CIRCRESAHA.111.300142
Abstract: Regulator of G-protein signaling 5 (RGS5) modulates G-protein-coupled receptor signaling and is prominently expressed in arterial smooth muscle cells. Our group first reported that RGS5 is important in vascular remodeling during tumor angiogenesis. We hypothesized that RGS5 may play an important role in vessel wall remodeling and blood pressure regulation. To demonstrate that RGS5 has a unique and nonredundant role in the pathogenesis of hypertension and to identify crucial RGS5-regulated signaling pathways. We observed that arterial RGS5 expression is downregulated with chronically elevated blood pressure after angiotensin II infusion. Using a knockout mouse model, radiotelemetry, and pharmacological inhibition, we subsequently showed that loss of RGS5 results in profound hypertension. RGS5 signaling is linked to the renin–angiotensin system and directly controls vascular resistance, vessel contractility, and remodeling. RGS5 deficiency aggravates pathophysiological features of hypertension, such as medial hypertrophy and fibrosis. Moreover, we demonstrate that protein kinase C, mitogen-activated protein kinase/extracellular signal–regulated kinase, and Rho kinase signaling pathways are major effectors of RGS5-mediated hypertension. Loss of RGS5 results in hypertension. Loss of RGS5 signaling also correlates with hyper-responsiveness to vasoconstrictors and vascular stiffening. This establishes a significant, distinct, and causal role of RGS5 in vascular homeostasis. RGS5 modulates signaling through the angiotensin II receptor 1 and major Gα q -coupled downstream pathways, including Rho kinase. So far, activation of RhoA/Rho kinase has not been associated with RGS molecules. Thus, RGS5 is a crucial regulator of blood pressure homeostasis with significant clinical implications for vascular pathologies, such as hypertension.
Applying Best Practice Online Learning, Teaching, and Support to Intensive Online Environments: An Integrative Review
Publisher: Frontiers Media SA
Date: 21-11-2017
Hypoxia increases the sensitivity of the L-type Ca2+current to β-adrenergic receptor stimulation via a C2 region-containing protein kinase C isoform
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-12-2000
DOI: 10.1161/01.RES.87.12.1164
Abstract: Abstract —The effects of hypoxia on the L-type Ca 2+ current ( I Ca-L ) in the absence and presence of the β-adrenergic receptor agonist isoproterenol (Iso) were examined. Exposing guinea pig ventricular myocytes to hypoxia alone resulted in a reversible inhibition of basal I Ca-L . When cells were exposed to Iso in the presence of hypoxia, the K 0.5 for activation of I Ca-L by Iso was significantly decreased from 5.3±0.7 to 1.6±0.1 nmol/L. The membrane-impermeant thiol-specific oxidizing compound 5,5′-dithio-bis(2-nitrobenzoic acid) (DTNB) attenuated the inhibition of basal I Ca-L by hypoxia 81.3±9.4% but had no effect on the increase in sensitivity of I Ca-L to Iso. In addition, DTT mimicked the effects of hypoxia on basal I Ca-L and the increase in sensitivity to Iso. Neither the inhibitors of guanylate cyclase LY-83583 or methylene blue nor the NO synthase inhibitor N G -monomethyl- l -arginine monoacetate had any effect on the basal inhibition of I Ca-L or the decrease in K 0.5 for activation of I Ca-L by Iso during hypoxia. However, the protein kinase C (PKC) inhibitors bisindolylmaleimide I and Gö 7874 significantly attenuated the increase in sensitivity of I Ca-L to Iso. More specifically, the response was attenuated when cells were dialyzed with a peptide inhibitor of the C2 region–containing classical PKC isoforms. The same effect was not observed with the PKCε peptide inhibitor. These results suggest that hypoxia regulates I Ca-L through the following 2 distinct mechanisms: direct inhibition of basal I Ca-L and an indirect effect on the sensitivity of the channel to β-adrenergic receptor stimulation that is mediated through a classical PKC isoform.
Myeloperoxidase-derived oxidants inhibit sarco/endoplasmic reticulum Ca2+-ATPase activity and perturb Ca2+homestasis in human coronary artery endothelial cells
Publisher: Elsevier BV
Date: 03-2012
Identification of a novel cAMP dependent protein kinase A phosphorylation site on the human cardiac calcium channel
Publisher: Springer Science and Business Media LLC
Date: 09-11-2017
DOI: 10.1038/S41598-017-15087-0
Abstract: The “Fight or Flight” response is elicited by extrinsic stress and is necessary in many species for survival. The response involves activation of the β-adrenergic signalling pathway. Surprisingly the mechanisms have remained unresolved. Calcium influx through the cardiac L-type Ca 2+ channel (Ca v 1.2) is absolutely required. Here we identify the functionally relevant site for PKA phosphorylation on the human cardiac L-type Ca 2+ channel pore forming α1 subunit using a novel approach. We used a cell free system where we could assess direct effects of PKA on human purified channel protein function reconstituted in proteoliposomes. In addition to assessing open probability of channel protein we used semi-quantitative fluorescent phosphoprotein detection and MS/MS mass spectrometry analysis to demonstrate the PKA specificity of the site. Robust increases in frequency of channel openings were recorded after phosphorylation of the long and short N terminal isoforms and the channel protein with C terminus truncated at aa1504. A protein kinase A anchoring protein (AKAP) was not required. We find the novel PKA phosphorylation site at Ser1458 is in close proximity to the Repeat IV S6 region and induces a conformational change in the channel protein that is necessary and sufficient for increased calcium influx through the channel.
α1 -adrenergic inhibition of the β-adrenergically activated Cl-current in guinea pig ventricular myocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1996
Abstract: Abstract α-Adrenergic receptor stimulation regulates the activity of a number of different cardiac ion channels, including those underlying one or more distinct Cl − conductances. The whole-cell patch-cl technique was used in the present study to investigate the effects of α-adrenergic stimulation on the β-adrenergically regulated Cl − current in guinea pig ventricular myocytes. Neither α 1 -adrenergic receptor stimulation with methoxamine (25 to 500 μmol/L) nor direct activation of endogenous protein kinase C (PKC) with phorbol 12,13-dibutyrate (PDBu, 100 nmol/L) evoked a Cl − current. On the contrary, the Cl − current activated by 30 nmol/L isoproterenol was inhibited by methoxamine, with an EC 50 of 6.7±2.6 μmol/L, and this response was blocked by prazosin, an α 1 -adrenergic receptor antagonist. Prazosin also decreased the EC 50 for current activation by norepinephrine from 53±7.1 to 18±3.8 nmol/L, demonstrating that the ability of this endogenous neurotransmitter to activate the Cl − current through β-adrenergic receptor stimulation is limited by its intrinsic ability to also activate α-adrenergic receptors. Methoxamine did not inhibit the Cl − current evoked by either direct activation of adenylate cyclase with forskolin or inhibition of phosphodiesterase activity with 3-isobutyl-1-methylxanthine, indicating that α-adrenergic stimulation inhibits β-adrenergic responses at a point upstream of adenylate cyclase activation. Methoxamine also did not inhibit the Cl − current activated by histamine, suggesting that α-adrenergic stimulation specifically inhibits β-adrenergic receptor–mediated responses. The inhibitory effect of methoxamine was not mimicked by PDBu, and it persisted in the presence of bisindolylmaleimide, a selective PKC inhibitor. However, methoxamine inhibition of the isoproterenol-activated Cl − current was sensitive to pertussis toxin. These results suggest that α-adrenergic receptor stimulation inhibits the β-adrenergically activated Cl − current, demonstrating a novel mechanism by which α-adrenergic receptors may regulate ion channel activity in the heart.
Contributions of Ion Channel Currents to Ventricular Action Potential Changes and Induction of Early Afterdepolarizations During Acute Hypoxia
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-12-2009
DOI: 10.1161/CIRCRESAHA.109.202267
Abstract: Rationale: Variability in delivery of oxygen can lead to electric instability in the myocardium and the generation of arrhythmias. In addition ischemic heart disease and angina are associated with an increase in circulating catecholamines that further increases the risk of developing ventricular tachyarrhythmias. Objective: We investigated the net effects of acute hypoxia and catecholamines on the cardiac action potential. Methods and Results: We incorporated all published data on the effects of hypoxia on the late Na + current ( I Na-L ), the fast Na + current ( I Na ), the basal L-type Ca 2+ channel current ( I Ca-L ), and the slow ( I Ks ) and rapid components of the delayed rectifier K + -current ( I Kr ) in the absence and presence of β-adrenergic receptor (β-AR) stimulation into the Luo–Rudy model of the action potential. Hypoxia alone had little effect on the action potential configuration or action potential duration. However in the presence of β-AR stimulation, hypoxia caused a prolongation of the action potential and early afterdepolarizations (EADs) and spontaneous tachycardia were induced. Experiments performed in guinea pig ventricular myocytes confirmed the modeling results. Conclusions: EADs occur predominantly because of the increased sensitivity of I Ca-L to β-AR stimulation during hypoxia. β-AR stimulation is necessary to induce EADs as EADs are never observed during hypoxia in the absence of β-AR stimulation.
Dystrophic cardiomyopathy—potential role of calcium in pathogenesis, treatment and novel therapies
Publisher: MDPI AG
Date: 24-03-2017
DOI: 10.3390/GENES8040108
TGF‐β‐induced fibrotic stress increases G‐quadruplex formation in human fibroblasts
Publisher: Wiley
Date: 11-2019
Abstract: Scar formation after wound healing is a major medical problem. A better understanding of the dynamic nuclear architecture of the genome during wound healing could provide insights into the underlying pathophysiology and enable novel therapeutic strategies. Here, we demonstrate that TGF-β-induced fibrotic stress increases formation of the dynamic secondary DNA structures called G-quadruplexes in skin fibroblasts, which is coincident with increased expression of collagen 1. This G-quadruplex formation is attenuated by a small molecule inhibitor of intracellular Ca
Introducing the Western Australian Cardiovascular Research Alliance (WACRA) – Why?, Why Now? And How Can Government Help?
Publisher: Elsevier BV
Date: 10-2021
PTCD1 Is Required for 16S rRNA Maturation Complex Stability and Mitochondrial Ribosome Assembly
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1016/J.CELREP.2018.03.033
Abstract: The regulation of mitochondrial RNA life cycles and their roles in ribosome biogenesis and energy metabolism are not fully understood. We used CRISPR/Cas9 to generate heart- and skeletal-muscle-specific knockout mice of the pentatricopeptide repeat domain protein 1, PTCD1, and show that its loss leads to severe cardiomyopathy and premature death. Our detailed transcriptome-wide and functional analyses of these mice enabled us to identify the molecular role of PTCD1 as a 16S rRNA-binding protein essential for its stability, pseudouridylation, and correct biogenesis of the mitochondrial large ribosomal subunit. We show that impaired mitoribosome biogenesis can have retrograde signaling effects on nuclear gene expression through the transcriptional activation of the mTOR pathway and upregulation of cytoplasmic protein synthesis and pro-survival factors in the absence of mitochondrial translation. Taken together, our data show that impaired assembly of the mitoribosome exerts its consequences via differential regulation of mitochondrial and cytoplasmic protein synthesis.
The impact of non-severe burn injury on cardiac function and long-term cardiovascular pathology
Publisher: Springer Science and Business Media LLC
Date: 03-10-2016
DOI: 10.1038/SREP34650
Abstract: Severe burn injury significantly affects cardiovascular function for up to 3 years. However, whether this leads to long-term pathology is unknown. The impact of non-severe burn injury, which accounts for over 80% of admissions in developed countries, has not been investigated. Using a rodent model of non-severe burn injury with subsequent echocardiography we showed significantly increased left ventricular end systolic diameter (LVESD) and ventricular wall thickness at up to 3 months post-injury. Use of propranolol abrogated the changes in cardiac measures observed. Subsequently we investigated changes in a patient cohort with non-severe injury. Echocardiography measured at baseline and at 3 months post-injury showed increased LVESD at 3 months and significantly decreased posterior wall diameter. Finally, 32 years of Western Australian hospital records were used to investigate the incidence of cardiovascular disease admissions after burn injury. People who had experienced a burn had increased hospital admissions and length of stay for cardiovascular diseases when compared to a matched uninjured cohort. This study presents animal, patient and population data that strongly suggest non-severe burn injury has significant effects on cardiovascular function and long-term morbidity in some burn patients. Identification of patients at risk will promote better intervention and outcomes for burn patients.
What Cardiologists Should Know About Calcium Ion Channels and Their Regulation by Reactive Oxygen Species
Publisher: Elsevier BV
Date: 10-2007
DOI: 10.1016/J.HLC.2007.01.005
Abstract: Ion channels underlie the electrical activity of cells. Calcium channels have a unique functional role, because not only do they participate in this activity, they form the means by which electrical signals are converted to responses within the cell. Calcium channels play an integral role in excitation in the heart and shaping the cardiac action potential. In addition, calcium influx through calcium channels is responsible for initiating contraction. Abnormalities in calcium homeostasis underlie cardiac arrhythmia, contractile dysfunction and cardiac remodelling. Reactive oxygen species participate in the development of pathology by altering the redox state of regulatory proteins. There is now good evidence that reactive oxygen species regulate the function of calcium channels. In this mini-review, the evidence for regulation of calcium channels by reactive oxygen species and implications with respect to pathology are presented. Calcium channels may represent a target for intervention during hypoxic trigger of arrhythmia or chronic pathological remodelling.
A novel antimicrobial agent reduces oxidative stress in cells
Publisher: Royal Society of Chemistry (RSC)
Date: 2013
DOI: 10.1039/C3RA40658J
What's the difference? Understanding sexual dimorphism in physiology
Publisher: Wiley
Date: 23-01-2023
DOI: 10.1113/JP284342
Role of NAD(P)H oxidase in the regulation of cardiac L-type Ca2+channel function during acute hypoxia
Publisher: Oxford University Press (OUP)
Date: 09-2005
DOI: 10.1016/J.CARDIORES.2005.04.025
Abstract: The role of NAD(P)H oxidase in regulating cellular production of reactive oxygen species (ROS) and the L-type Ca2+ channel during acute hypoxia was examined in adult ventricular myocytes from guinea pig. The fluorescent indicator dihydroethidium (DHE) was used to detect superoxide and the response of the L-type Ca2+ channel to beta-adrenergic receptor stimulation was used as a functional reporter since hypoxia increases the sensitivity of the L-type Ca2+ channel (I(Ca-L)) to isoproterenol (Iso). Hypoxia caused a 41.2+/-5.2% decrease in the rate of the DHE signal (n=21 p<0.01). Of the classical NAD(P)H oxidase inhibitors, DPI but not apocynin mimicked the effect of hypoxia on the sensitivity of I(Ca-L) to Iso. However, the potent NAD(P)H oxidase agonist angiotensin II had no effect on cellular superoxide or the sensitivity of I(Ca-L) to Iso. Although DPI inhibits NAD(P)H oxidase, it also decreased superoxide in isolated mitochondria in a concentration-dependent manner. Partial inhibition of mitochondrial function with nanomolar concentrations of FCCP or myxothiazol mimicked the effect of hypoxia on cellular superoxide and the sensitivity of I(Ca-L) to Iso. In addition, hypoxia caused a 69.3+/-0.8% decrease in superoxide in isolated mitochondria (n=4 p<0.01), providing direct evidence for a role for the mitochondria. Our data suggest that mitochondria appear to be involved in oxygen sensing, regulation of cellular ROS, and the function of I(Ca-L) during acute hypoxia in cardiac myocytes and NAD(P)H oxidase does not appear to contribute substantially.
The most recent burst of star formation in the massive elliptical galaxy NGC 1052
Publisher: Oxford University Press (OUP)
Date: 14-12-2011
Hypoxia alters the sensitivity of the L-type Ca2+channel to α-adrenergic receptor stimulation in the presence of β-adrenergic receptor stimulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 25-05-2001
Abstract: Abstract —The effects of α-adrenergic receptor (α-AR) stimulation alone and the effects in the presence of β-adrenergic receptor (β-AR) stimulation were examined on L-type Ca 2+ currents ( I Ca-L ) in the absence and presence of hypoxia. The α-AR agonist methoxamine either had no effect or had a slight inhibitory effect on basal I Ca-L in the absence and presence of hypoxia. Hypoxia significantly decreased the K 0.5 for activation of I Ca-L by norepinephrine from 79.8±6.6 to 13.3±0.7 nmol/L. To determine whether hypoxia specifically altered the sensitivity of the channel to α-AR stimulation, cells were exposed to increasing concentrations of methoxamine in the presence of 100 nmol/L isoproterenol (Iso). In the absence of hypoxia, methoxamine inhibited the Iso-activated I Ca-L in a concentration-dependent manner with an EC 50 of 86.9±9.9 μmol/L. However, in the presence of hypoxia, the EC 50 for inhibition of I Ca-L by methoxamine was significantly increased to 266.7±10.8 μmol/L. Methoxamine had little effect on I Ca-L activated by forskolin or histamine in the absence or presence of hypoxia. In addition, inhibition of protein kinase C by bisindolylmaleimide 1 or protein kinase C β peptide inhibitor had no effect on the methoxamine-induced antagonism of I Ca-L in the absence or presence of hypoxia. The tyrosine kinase inhibitor genistein attenuated the methoxamine response in nonhypoxic cells only. However, during hypoxia it was attenuated with the phospholipase A 2 inhibitors mepacrine and indomethacin. These findings represent a novel regulation of the L-type Ca 2+ channel by the phospholipase A 2 pathway and illustrate the complexity of regulation of the channel under hypoxic conditions.
MscS, the bacterial mechanosensitive channel of small conductance
Publisher: Elsevier BV
Date: 2008
DOI: 10.1016/J.BIOCEL.2007.03.013
Abstract: The mechanosensitive channel of small conductance, MscS, is one of the most extensively studied MS channels to date. Past and present research involves the discovery of its physiological role as an emergency valve in prokaryotes up to detailed investigations of its conductive properties and gating mechanism. In this review, we summarize the findings on its structure and function obtained by experimental and theoretical approaches. A special focus is given to its pharmacology, since various compounds have been shown to affect the activity of this channel. These compounds have particularly been helpful for understanding the interaction of MscS with the lipid bilayer, as well as recognizing the potential of this channel as a target for novel types of antibiotics.
A common genetic variant of a mitochondrial RNA processing enzyme predisposes to insulin resistance
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-09-2021
Abstract: A variant in an RNA processing enzyme predisposes to insulin resistance by reducing calcium release and insulin secretion.
Acute hypoxia differentially regulates K+channels. Implications with respect to cardiac arrhythmia
Publisher: Springer Science and Business Media LLC
Date: 22-02-2005
DOI: 10.1007/S00249-005-0462-3
Abstract: The first ion channels demonstrated to be sensitive to changes in oxygen tension were K(+) channels in glomus cells of the carotid body. Since then a number of hypoxia-sensitive ion channels have been identified. However, not all K(+) channels respond to hypoxia alike. This has raised some debate about how cells detect changes in oxygen tension. Because ion channels respond rapidly to hypoxia it has been proposed that the channel is itself an oxygen sensor. However, channel function can also be modified by thiol reducing and oxidizing agents, implicating reactive oxygen species as signals in hypoxic events. Cardiac ion channels can also be modified by hypoxia and redox agents. The rapid and slow components of the delayed rectifier K(+) channel are differentially regulated by hypoxia and beta-adrenergic receptor stimulation. Mutations in the genes that encode the subunits for the channel are associated with Long QT syndrome and sudden cardiac death. The implications with respect to effects of hypoxia on the channel and triggering of cardiac arrhythmia will be discussed.
Increased Arrhythmic Activity is associated With Altered Ion Channel Expression, Localisation and Function in AMHC403/+ Hypertrophic Hearts
Publisher: Elsevier BV
Date: 2020
Role of the cytoskeleton in communication between L-type Ca<sup>2+</sup> channels and mitochondria
Publisher: Wiley
Date: 30-03-2013
Abstract: The L-type Ca(2+) channel is the main route for Ca(2+) entry into cardiac myocytes, which is essential for the maintenance of cardiac excitation and contraction. Alterations in L-type Ca(2+) channel activity and Ca(2+) homeostasis have been implicated in the development of cardiomyopathies. Cardiac excitation and contraction is fuelled by ATP, synthesized predominantly by the mitochondria via the Ca(2+)-dependent process oxidative phosphorylation. Mitochondrial reactive oxygen species (ROS) are by-products of oxidative phosphorylation and are associated with the development of cardiac pathology. The cytoskeleton plays a role in the communication of signals from the plasma membrane to intracellular organelles. There is good evidence that both L-type Ca(2+) channel activity and mitochondrial function can be modulated by changes in the cytoskeletal network. Activation of the L-type Ca(2+) channel can regulate mitochondrial function through cytoskeletal proteins as a result of transmission of movement from the β(2)-subunit of the channel that occurs during activation and inactivation of the channel. An association between cytoskeletal proteins and the mitochondrial voltage-dependent anion channel (VDAC) may play a role in this response. The L-type Ca(2+) channel is the initiator of contraction in cardiac muscle and the VDAC is responsible for regulating mitochondrial ATP/ADP trafficking. This article presents evidence that a functional coupling between L-type Ca(2+) channels and mitochondria may assist in meeting myocardial energy demand on a beat-to-beat basis.
L-type Ca2+ channel contributes to alterations in mitochondrial calcium handling in the mdx ventricular myocyte
Publisher: American Physiological Society
Date: 15-03-2013
DOI: 10.1152/AJPHEART.00700.2012
Abstract: The L-type Ca 2+ channel is the main route for calcium entry into cardiac myocytes, and it is essential for contraction. Alterations in whole cell L-type Ca 2+ channel current and Ca 2+ homeostasis have been implicated in the development of cardiomyopathies. Cytoskeletal proteins can influence whole cell L-type Ca 2+ current and mitochondrial function. Duchenne muscular dystrophy is a fatal X-linked disease that leads to progressive muscle weakness due to the absence of cytoskeletal protein dystrophin. This includes dilated cardiomyopathy, but the mechanisms are not well understood. We sought to identify the effect of alterations in whole cell L-type Ca 2+ channel current on mitochondrial function in the murine model of Duchenne muscular dystrophy ( mdx). Activation of the L-type Ca 2+ channel with the dihydropyridine agonist BayK(−) caused a significantly larger increase in cytosolic Ca 2+ in mdx vs. wild-type ( wt) ventricular myocytes. Consistent with elevated cytosolic Ca 2+ , resting mitochondrial Ca 2+ , NADH, and mitochondrial superoxide were significantly greater in mdx vs. wt myocytes. Activation of the channel with BayK(−) caused a further increase in mitochondrial Ca 2+ , NADH, and superoxide in mdx myocytes. The ratios of the increases were similar to the ratios recorded in wt myocytes. In mitochondria isolated from 8-wk-old mdx hearts, respiration and mitochondrial electron transport chain complex activity were similar to mitochondria isolated from wt hearts. We conclude that mitochondria function at a higher level of resting calcium in the intact mdx myocyte and activation of the L-type Ca 2+ channel contributes to alterations in calcium handling by the mitochondria. This perturbation may contribute to the development of cardiomyopathy.
Targeting calcium and the mitochondria in prevention of pathology in the heart
Publisher: Bentham Science Publishers Ltd.
Date: 05-2011
DOI: 10.2174/138945011795378603
Abstract: Calcium is a key determinant of cardiac excitation, contraction and relaxation. Cardiac excitation and contraction is powered by ATP that is synthesized within mitochondria via a calcium-dependent process known as oxidative phosphorylation. During this process oxygen molecules within the mitochondria are converted to superoxide. Under physiological conditions, low levels of ROS are required to maintain normal cellular function. This is achieved as a result of a balance between ROS formation and amelioration by antioxidants. Uninhibited increases in ROS production lead to oxidative stress. Large increases in ROS are associated with damage to mitochondria, DNA, proteins and lipids. In the heart this ultimately leads to apoptosis and loss of myocytes. However sub-lethal increases in ROS can activate hypertrophic signaling kinases and transcription factors including NFAT, CaMK and serine-threonine and tyrosine kinases. Calcium is also an important signaling molecule and a mediator of hypertrophic signaling pathways. ROS and calcium appear to participate as partners in pathological remodeling but their interaction and early mechanisms associated with the development of cardiac hypertrophy are poorly understood. An increase in cytoplasmic calcium can potentiate cellular oxidative stress via effects on mitochondrial metabolism. In addition oxidative stress can regulate the function of calcium channels and transporters. We discuss the evidence for calcium transporting proteins and the mitochondria in oxidative stress responses and propose sites to target in the prevention of cardiac hypertrophy.
The cardiac L-type calcium channel alpha subunit is a target for direct redox modification during oxidative stress—the role of cysteine residues in the alpha interacting domain
Publisher: Wiley
Date: 20-09-2017
Abstract: Cardiovascular disease is the leading cause of death in the Western world. The incidence of cardiovascular disease is predicted to further rise with the increase in obesity and diabetes and with the aging population. Even though the survival rate from ischaemic heart disease has improved over the past 30 years, many patients progress to a chronic pathological condition, known as cardiac hypertrophy that is associated with an increase in morbidity and mortality. Reactive oxygen species (ROS) and calcium play an essential role in mediating cardiac hypertrophy. The L-type calcium channel is the main route for calcium influx into cardiac myocytes. There is now good evidence for a direct role for the L-type calcium channel in the development of cardiac hypertrophy. Cysteines on the channel are targets for redox modification and glutathionylation of the channel can modulate the function of the channel protein leading to the onset of pathology. The cysteine responsible for modification of L-type calcium channel function has now been identified. Detailed understanding of the role of cysteines as possible targets during oxidative stress may assist in designing therapy to prevent the development of hypertrophy and heart failure.
Mechanosensation mediates volume adaptation of cardiac cells and spheroids in 3D
Publisher: Elsevier BV
Date: 12-2022
Identification of a novel cAMP dependent protein kinase A phosphorylation site on the human cardiac calcium channel (vol 7, 15118, 2017)
Publisher: Springer Science and Business Media LLC
Date: 03-05-2018
DOI: 10.1038/S41598-018-24792-3
Abstract: A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
Myeloperoxidase-derived Oxidants Inhibit SERCA Activity and Perturb Ca2+ Homeostasis in Human Coronary Artery Endothelial Cells
Publisher: Elsevier BV
Date: 11-2012
The innermost globular clusters of M87
Publisher: Oxford University Press (OUP)
Date: 11-06-2014
DOI: 10.1093/MNRAS/STU948
Interrogating cardiac muscle cell mechanobiology on stiffness gradient hydrogels
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1BM01061A
Abstract: Mechanobiology of H9C2 cells and neonatal cardiomyocytes mapped using stiffness gradient hydrogels with a range of extracellular matrix coatings, revealing stiffness-driven trends in cell morphology, YAP and MRTF-A expression.
The Role of the L-Type Ca2+ Channel in Altered Metabolic Activity in a Murine Model of Hypertrophic Cardiomyopathy
Publisher: Elsevier BV
Date: 2016
Ex Vivo Effect of 60 GHz MMW radiation on Leech Neuron Intracellular Calcium Alteration
Publisher: IEEE
Date: 21-09-2020
A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology
Publisher: Springer Science and Business Media LLC
Date: 03-01-2023
DOI: 10.1038/S42003-022-04278-9
Abstract: Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young’s Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy ( cTnI-G203S ). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key ‘linker’ sites in this schema that may represent potential therapeutic targets.
Differential regulation of the slow and rapid components of guinea-pig cardiac delayed rectifier K+ channels by hypoxia
Publisher: Wiley
Date: 02-2004
Impaired calcium handling and mitochondrial metabolic dysfunction as early markers of hypertrophic cardiomyopathy
Publisher: Elsevier BV
Date: 04-2019
DOI: 10.1016/J.ABB.2019.03.006
Abstract: Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder, characterised by myocyte remodeling, disorganisation of sarcomeric proteins, impaired energy metabolism and altered cardiac contractility. Gene mutations encoding cardiac contractile proteins account for 60% of HCM aetiology. Current drug therapy including L-type calcium channel antagonists, are used to manage symptoms in patients with overt HCM, but no treatment exists that can reverse or prevent the cardiomyopathy. Design of effective drug therapy will require a clear understanding of the early pathophysiological mechanisms of the disease. Numerous studies have investigated specific aspects of HCM pathophysiology. This review brings these findings together, in order to develop a holistic understanding of the early pathophysiological mechanisms of the disease. We focus on gene mutations in cardiac myosin binding protein-C, β-cardiac myosin heavy chain, cardiac troponin I, and cardiac troponin T, that comprise the majority of all HCM sarcomeric gene mutations. We find that although some similarities exist, each mutation leads to mutation-specific alterations in calcium handling, myofilament calcium sensitivity and mitochondrial metabolic function. This may contribute to the observed clinical phenotypic variability in sarcomeric-related HCM. An understanding of early mutation-specific mechanisms of the disease may provide useful markers of disease progression, and inform therapeutic design.
The design and testing of multifunctional nanoparticles for drug delivery applications
Publisher: Pan Stanford
Date: 26-01-2016
DOI: 10.1201/B20041-2
Mitochondria at the Crossroads of Survival and Demise
Publisher: Hindawi Limited
Date: 04-12-2019
DOI: 10.1155/2019/2608187
L-type Ca2+ channel–mediated Ca2+ influx adjusts neuronal mitochondrial function to physiological and pathophysiological conditions
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-02-2020
DOI: 10.1126/SCISIGNAL.AAW6923
Abstract: L-type Ca 2+ channel activity confers neuroprotection by inducing the ATP synthase to operate in reverse mode.
The L-type Ca2+ Channel as a Potential Mediator of Pathology During Alterations in Cellular Redox State
Publisher: Elsevier BV
Date: 02-2009
DOI: 10.1016/J.HLC.2008.11.004
Abstract: The L-type Ca(2+) channel is the main route for calcium influx into cardiac myocytes and an important determinant of calcium homeostasis. There is now considerable evidence that the function of the L-type Ca(2+) channel is influenced by the cell's redox state. Reactive oxygen species such as hydrogen peroxide and superoxide can regulate biological function by directly altering the thiol redox state of proteins. Under conditions where cellular redox state varies, L-type Ca(2+) channel function and diastolic calcium levels can be significantly altered. This article will present the evidence for alterations in L-type Ca(2+) channel function by reactive oxygen species and the potential role for the channel in development of acute electrophysiological instability or chronic pathological remodelling under conditions of persistent oxidative stress.
Calcium regulatory proteins as therapeutic targets
Publisher: Bentham Science Publishers Ltd.
Date: 05-2011
Millimeter wave radiation activates leech nociceptors via TRPV1-like receptor sensitization
Publisher: Elsevier BV
Date: 06-2019
The L-type Ca2 + channel
Publisher: Informa UK Limited
Date: 03-08-2017
Characterising the Effects of a Peptide Directed Against the L-Type Ca2+ Channel on Mitochondrial Function in Hypertrophic Cardiomyopathy
Publisher: Elsevier BV
Date: 02-1998
Auto-regulation in the powerhouse
Publisher: eLife Sciences Publications, Ltd
Date: 10-07-2017
DOI: 10.7554/ELIFE.28757
Abstract: Mitochondrial flashes have a central role in ensuring that ATP levels remain constant in heart cells.
The surface electronic structure of silicon terminated (100) diamond.
Publisher: IOP Publishing
Date: 23-05-2016
DOI: 10.1088/0957-4484/27/27/275201
Abstract: A combination of synchrotron-based x-ray spectroscopy and contact potential difference measurements have been used to examine the electronic structure of the (3 × 1) silicon terminated (100) diamond surface under ultra high vacuum conditions. An occupied surface state which sits 1.75 eV below the valence band maximum has been identified, and indications of mid-gap unoccupied surface states have been found. Additionally, the pristine silicon terminated surface is shown to possess a negative electron affinity of -0.86 ± 0.1 eV.
Preventative therapeutic approaches for hypertrophic cardiomyopathy
Publisher: Wiley
Date: 07-09-2020
DOI: 10.1113/JP279410
Abstract: Sarcomeric gene mutations are associated with the development of hypertrophic cardiomyopathy (HCM). Current drug therapeutics for HCM patients are effective in relieving symptoms, but do not prevent or reverse disease progression. Moreover, due to heterogeneity in the clinical manifestations of the disease, patients experience variable outcomes in response to therapeutics. Mechanistically, alterations in calcium handling, sarcomeric disorganization, energy metabolism and contractility participate in HCM disease progression. While some similarities exist, each mutation appears to lead to mutation‐specific pathophysiology. Furthermore, these alterations may precede or proceed development of the pathology. This review assesses the efficacy of HCM therapeutics from studies performed in animal models of HCM and human clinical trials. Evidence suggests that a preventative rather than corrective therapeutic approach may be more efficacious in the treatment of HCM. In addition, a clear understanding of mutation‐specific mechanisms may assist in informing the most effective therapeutic mode of action. image
The SED of low-luminosity AGNs at high-spatial resolution
Publisher: IOP Publishing
Date: 30-07-2012
How does the heart sense changes in oxygen tension: A role for ion channels?
Publisher: Mary Ann Liebert Inc
Date: 20-02-2015
Abstract: Oxygen plays a key role in cellular metabolism and function. Oxygen delivery to cells is crucial, and a lack of oxygen such as that which occurs during myocardial infarction can be lethal. Cells should, therefore, be able to respond to changes in oxygen tension. Since the first studies examining the acute cellular effect of hypoxia on activation of transmitter release from glomus or type I chemoreceptor cells, it is now known that virtually all cells are able to respond to changes in oxygen tension. Despite advances made in characterizing hypoxic responses, the identity of the "oxygen sensor" remains debated. Recently, more evidence has evolved as to how cardiac myocytes sense acute changes in oxygen. This review will examine the available evidence in support of acute oxygen-sensing mechanisms providing a brief historical perspective and then more detailed insights into the heart and the role of cardiac ion channels in hypoxic responses. A further understanding of these cellular processes should result in interventions that assist in preventing the deleterious effects of acute changes in oxygen tension such as alterations in contractile function and cardiac arrhythmia.
Transient exposure to hydrogen peroxide causes an increase in mitochondria-derived superoxide as a result of sustained alteration in L-type Ca2+ channel function in the absence of apoptosis in ventricular myocytes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-04-2007
DOI: 10.1161/01.RES.0000263010.19273.48
Abstract: We sought to understand the effect of a transient exposure of cardiac myocytes to H 2 O 2 at a concentration that did not induce apoptosis. Myocytes were exposed to 30 μmol/L H 2 O 2 for 5 minutes followed by 10 U/mL catalase for 5 minutes to degrade the H 2 O 2 . Cellular superoxide was measured using dihydroethidium. Transient exposure to H 2 O 2 caused a 66.4% increase in dihydroethidium signal compared with controls exposed to only catalase, without activation of caspase 3 or evidence of necrosis. The increase in dihydroethidium signal was attenuated by the mitochondrial inhibitors myxothiazol or carbonyl cyanide p -(trifluoromethoxy)phenyl-hydrazone and when calcium uptake by the mitochondria was inhibited with Ru360. We investigated the L-type Ca 2+ channel ( I Ca-L ) as a source of calcium influx. Nisoldipine, an inhibitor of I Ca-L , attenuated the increase in superoxide. Basal channel activity increased from 5.4 to 8.9 pA F. Diastolic calcium was significantly increased in quiescent and contracting myocytes after H 2 O 2 . The response of I Ca-L to β-adrenergic receptor stimulation was used as a functional reporter because decreasing intracellular H 2 O 2 alters the sensitivity of I Ca-L to isoproterenol. H 2 O 2 increased the K 0.5 required for activation of I Ca-L by isoproterenol from 5.8 to 27.8 nmol/L. This effect and the increase in basal current density persisted for several hours after H 2 O 2 . We propose that extracellular H 2 O 2 is associated with an increase in superoxide from the mitochondria caused by an increase in Ca 2+ influx from I Ca-L . The effect persists because a positive feedback exists among increased basal channel activity, elevated intracellular calcium, and superoxide production by the mitochondria.
A dendronized polymer variant that facilitates safe delivery of a calcium channel antagonist to the heart
Publisher: Elsevier BV
Date: 10-2020
Genistein increases the sensitivity of cardiac ion channels to β- adrenergic receptor stimulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 13-07-1998
Abstract: Abstract —The whole-cell patch-cl technique was used to monitor the effects of genistein, a tyrosine kinase inhibitor, on membrane currents recorded from isolated guinea pig ventricular myocytes. Under control conditions, genistein (50 μmol/L) did not activate the latent cAMP-regulated Cl − current ( I Cl ). However, in the presence of a subthreshold concentration (1 nmol/L) of the β-adrenergic agonist isoproterenol (Iso), genistein caused a near-maximal activation of this current. In the absence of genistein, Iso activated I Cl with an EC 50 of 5 nmol/L. In the presence of genistein, Iso activated I Cl with an EC 50 of 0.3 nmol/L. This facilitatory effect was not observed in the presence of daidzein (50 μmol/L), an analogue of genistein that only weakly inhibits tyrosine kinase activity. Furthermore, peroxovanadate, a potent inhibitor of phosphotyrosine phosphatase activity, inhibited I Cl activated by Iso alone, and it blocked the stimulatory effect of genistein in the presence of Iso. To determine whether the stimulatory effect of genistein was specific for I Cl , we also studied its action on the cAMP-regulated delayed rectifier K + current ( I K ) and L-type Ca 2+ current ( I Ca-L ) present in these cells. Basal I K and I Ca-L were partially (≈30% to 40%) inhibited by genistein. However, this inhibitory effect was mimicked by daidzein, suggesting that inhibition of tyrosine kinase activity is not involved. In addition to the nonspecific inhibitory effect, genistein also caused a significant increase in the β-adrenergic sensitivity of the unblocked cationic currents. In the absence of genistein, 1 nmol/L Iso had no effect on either I K or I Ca-L . However, in the presence of genistein, 1 nmol/L Iso significantly increased the magnitude of both currents. These results suggest that tyrosine kinase activity may play an important role in regulating β-adrenergic responsiveness of the heart.
Cellular and molecular changes to cortical neurons following low intensity repetitive magnetic stimulation at different frequencies
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.BRS.2014.09.012
Abstract: Repetitive transcranial magnetic stimulation is increasingly used as a treatment for neurological dysfunction. Therapeutic effects have been reported for low intensity rTMS (LI-rTMS) although these remain poorly understood. Our study describes for the first time a systematic comparison of the cellular and molecular changes in neurons in vitro induced by low intensity magnetic stimulation at different frequencies. We applied 5 different low intensity repetitive magnetic stimulation (LI-rMS) protocols to neuron-enriched primary cortical cultures for 4 days and assessed survival, and morphological and biochemical change. We show pattern-specific effects of LI-rMS: simple frequency pulse trains (10 Hz and 100 Hz) impaired cell survival, while more complex stimulation patterns (theta-burst and a biomimetic frequency) did not. Moreover, only 1 Hz stimulation modified neuronal morphology, inhibiting neurite outgrowth. To understand mechanisms underlying these differential effects, we measured intracellular calcium concentration during LI-rMS and subsequent changes in gene expression. All LI-rMS frequencies increased intracellular calcium, but rather than influx from the extracellular milieu typical of depolarization, all frequencies induced calcium release from neuronal intracellular stores. Furthermore, we observed pattern-specific changes in expression of genes related to apoptosis and neurite outgrowth, consistent with our morphological data on cell survival and neurite branching. Thus, in addition to the known effects on cortical excitability and synaptic plasticity, our data demonstrate that LI-rMS can change the survival and structural complexity of neurons. These findings provide a cellular and molecular framework for understanding what low intensity magnetic stimulation may contribute to human rTMS outcomes.
Cytoskeletal disarray increases arrhythmogenic vulnerability during sympathetic stimulation in a model of hypertrophic cardiomyopathy
Publisher: Springer Science and Business Media LLC
Date: 12-07-2023
DOI: 10.1038/S41598-023-38296-2
Abstract: Familial hypertrophic cardiomyopathy (FHC) patients are advised to avoid strenuous exercise due to increased risk of arrhythmias. Mice expressing the human FHC-causing mutation R403Q in the myosin heavy chain gene ( MYH6 ) recapitulate the human phenotype, including cytoskeletal disarray and increased arrhythmia susceptibility. Following in vivo administration of isoproterenol, mutant mice exhibited tachyarrhythmias, poor recovery and fatigue. Arrhythmias were attenuated with the β-blocker atenolol and protein kinase A inhibitor PKI. Mutant cardiac myocytes had significantly prolonged action potentials and triggered automaticity due to reduced repolarization reserve and connexin 43 expression. Isoproterenol shortened cycle length, and escalated electrical instability. Surprisingly isoproterenol did not increase Ca V 1.2 current. We found alterations in Ca V 1.2-β1 adrenergic receptor colocalization assessed using super-resolution nanoscopy, and increased Ca V 1.2 phosphorylation in mutant hearts. Our results reveal for the first time that altered ion channel expression, co-localization and β-adrenergic receptor signaling associated with myocyte disarray contribute to electrical instability in the R403Q mutant heart.
Role of β1- and β2-adrenergic receptors in regulation of Cl- and Ca2+ channels in guinea pig ventricular myocytes
Publisher: American Physiological Society
Date: 10-1997
DOI: 10.1152/AJPHEART.1997.273.4.H1669
Abstract: The role of β 1 - and β 2 -adrenergic receptor stimulation in modulating adenosine 3′,5′-cyclic monophosphate (cAMP)-regulated Cl − and Ca 2+ currents was investigated with use of guinea pig ventricular myocytes. Activation of the Cl − current by the nonselective β-receptor agonist isoproterenol (Iso) was not affected by the β 2 -receptor antagonist ICI-118,551 (ICI), but it was blocked by the β 1 -receptor antagonist atenolol. The inability of β 2 -receptor stimulation to activate the Cl − current was confirmed by the lack of response to the selective β 2 -receptor agonists salbutamol and zinterol. Responses to β 2 -adrenergic receptor stimulation were also looked for in pertussis toxin (PTX)-treated myocytes because PTX increases the sensitivity of responses to Iso, and PTX has been reported to increase the responsiveness to β 2 - but not β 1 -receptor stimulation. PTX treatment increased the sensitivity of the Cl − current to activation by Iso in the presence of ICI, indicating that PTX increases β 1 -receptor responsiveness. PTX treatment also resulted in the ability of salbutamol to activate the Cl − current. However, the response to salbutamol was blocked by atenolol but not by appropriate concentrations of ICI, suggesting that salbutamol was activating β 1 -receptors. These results indicate that PTX treatment increases the sensitivity to β 1 -receptor stimulation, without affecting β 2 -responsiveness. To verify that the lack of response to β 2 -receptor stimulation was not unique to the Cl − current, the effects of β 2 -receptor agonists on the L-type Ca 2+ current were also examined. The Ca 2+ current was only affected by high concentrations of zinterol or salbutamol, and such responses were blocked by atenolol, but not by ICI, suggesting that activation of β 1 -receptors was involved. These results indicate that β 1 - but not β 2 -adrenergic receptor stimulation plays an important role in modulating the cAMP-regulated Cl − and Ca 2+ currents in guinea pig ventricular myocytes.
Regenerating optic axons restore topography after incomplete optic nerve injury
Publisher: Wiley
Date: 29-08-2007
DOI: 10.1002/CNE.21477
Abstract: Following complete optic nerve injury in a lizard, Ctenophorus ornatus, retinal ganglion cell (RGC) axons regenerate but fail to restore retinotectal topography unless animals are trained on a visual task (Beazley et al. [ 1997] J Comp Neurol 370:105-120, [2003] J Neurotrauma 20:1263-1270). Here we show that incomplete injury, which leaves some RGC axons intact, restores normal topography. Strict RGC axon topography allowed us to preserve RGC axons on one side of the nerve (projecting to medial tectum) while lesioning those on the other side (projecting to lateral tectum). Topography and response properties for both RGC axon populations were assessed electrophysiologically. The majority of intact RGC axons retained appropriate topography in medial tectum and had normal, consistently brisk, reliable responses. Regenerate RGC axons fell into two classes: those that projected topographically to lateral tectum with responses that tended to habituate and those that lacked topography, responded weakly, and habituated rapidly. Axon tracing by localized retinal application of carbocyanine dyes supported the electrophysiological data. RGC soma counts were normal in both intact and axotomized RGC populations, contrasting with the 30% RGC loss after complete injury. Unlike incomplete optic nerve injury in mammals, where RGC axon regeneration fails and secondary cell death removes many intact RGC somata, lizards experience a "win-win" situation: intact RGC axons favorably influence the functional outcome for regenerating ones and RGCs do not succumb to either primary or secondary cell death.
Fidelity and coordination of mitochondrial protein synthesis in health and disease
Publisher: Wiley
Date: 15-08-2021
DOI: 10.1113/JP280359
Abstract: The evolutionary acquisition of mitochondria has given rise to the ersity of eukaryotic life. Mitochondria have retained their ancestral α‐proteobacterial traits through the maintenance of double membranes and their own circular genome. Their genome varies in size from very large in plants to the smallest in animals and their parasites. The mitochondrial genome encodes essential genes for protein synthesis and has to coordinate its expression with the nuclear genome from which it sources most of the proteins required for mitochondrial biogenesis and function. The mitochondrial protein synthesis machinery is unique because it is encoded by both the nuclear and mitochondrial genomes thereby requiring tight regulation to produce the respiratory complexes that drive oxidative phosphorylation for energy production. The fidelity and coordination of mitochondrial protein synthesis are essential for ATP production. Here we compare and contrast the mitochondrial translation mechanisms in mammals and fungi to bacteria and reveal that their erse regulation can have unusual impacts on the health and disease of these organisms. We highlight that in mammals the rate of protein synthesis is more important than the fidelity of translation, enabling coordinated biogenesis of the mitochondrial respiratory chain with respiratory chain proteins synthesised by cytoplasmic ribosomes. Changes in mitochondrial protein fidelity can trigger the activation of the erse cellular signalling networks in fungi and mammals to combat dysfunction in energy conservation. The physiological consequences of altered fidelity of protein synthesis can range from liver regeneration to the onset and development of cardiomyopathy. image
Mutation in MRPS34 Compromises Protein Synthesis and Causes Mitochondrial Dysfunction
Publisher: Public Library of Science (PLoS)
Date: 27-03-2015
Loss of the RNA-binding protein TACO1 causes late-onset mitochondrial dysfunction in mice
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NCOMMS11884
Abstract: The recognition and translation of mammalian mitochondrial mRNAs are poorly understood. To gain further insights into these processes in vivo, we characterized mice with a missense mutation that causes loss of the translational activator of cytochrome oxidase subunit I (TACO1). We report that TACO1 is not required for embryonic survival, although the mutant mice have substantially reduced COXI protein, causing an isolated complex IV deficiency. We show that TACO1 specifically binds the mt-Co1 mRNA and is required for translation of COXI through its association with the mitochondrial ribosome. We determined the atomic structure of TACO1, revealing three domains in the shape of a hook with a tunnel between domains 1 and 3. Mutations in the positively charged domain 1 reduce RNA binding by TACO1. The Taco1 mutant mice develop a late-onset visual impairment, motor dysfunction and cardiac hypertrophy and thus provide a useful model for future treatment trials for mitochondrial disease.
Verapamil is less effective than triamcinolone for prevention of keloid scar recurrence after excision in a randomized controlled trial
Publisher: Medical Journals Sweden AB
Date: 2016
Abstract: A double-blind randomized controlled trial with a paired split-scar design compared verapamil, an L-type Ca2+ channel antagonist, and triamcinolone for prevention of keloid recurrence after excision. Ca2+ channel blocking activity of verapamil in keloid cells was explored. One keloid was excised per subject and each wound half randomized to receive intralesional injections of triamcinolone (10 mg/ml) or verapamil (2.5 mg/ml) at monthly intervals (4 doses). Interim analysis was performed after 14 subjects were completed. Survival analysis demonstrated significantly higher keloid recurrence with verapamil compared to triamcinolone 12 months post-surgery (log-rank test, p = 0.01) and higher overall risk of recurrence with verapamil (hazard ratio 8.44, 95% CI 1.62-44.05). The study was terminated early according to the stopping guideline (p < 0.05). Verapamil is safe but not as effective as triamcinolone in preventing keloid recurrence after excision. Further study is necessary to determine if clinical response to verapamil is linked to modulation of intracellular Ca2+.
A Review of in vitro Platforms for Understanding Cardiomyocyte Mechanobiology
Publisher: Frontiers Media SA
Date: 05-06-2019
Nanoparticle-mediated internalisation and release of a calcium channel blocker
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2RA21058D
A Self-Managed Online Mindfulness Program in a University-Wide Learning Management System Orientation Site: A Real-World Ecological Validation Study
Publisher: Frontiers Media SA
Date: 06-05-2022
DOI: 10.3389/FPSYG.2022.869765
Abstract: The efficacy of mindfulness-based interventions in randomised-controlled trials and large experimental studies has been demonstrated in university student populations. Whilst these investigations have provided insight into the nature of the delivery of mindfulness-based practices, there has been little research in the implementation of self-managed online student wellbeing and mindfulness programs at university. This ecological validation study conducted in 2020 evaluated a real-world implementation of a large, university-wide, online mindfulness-based program that was accessible fully online via the tertiary institutions’ Learning Management System (LMS) student orientation site. The total s le included 833 participants from a range of disciplines and faculties at Monash University, Australia. At the end of the study, 236 (28.3%) participants were retained and completed the follow-up survey. Participants had the option to engage with the fully self-managed online mindfulness program for a 12-week semester. The mindfulness practices were pre-recorded, audio-guided sessions, and 10–15 min in length. Baseline and end of semester questionnaires included the 14-item Warwick-Edinburgh Mental Wellbeing Scale, 10-item Perceived Stress Scale and the 18-item Five Facet Mindfulness Questionnaire. Participants who engaged with the mindfulness program over 3 or more weeks showed significant improvements in all three outcome measures, and all participants showed significant improvements in wellbeing at the end of semester. Learning analytics obtained via the LMS revealed that 58.6% ( n = 489) had not logged into the mindfulness program at all, almost a third (31.0%, n = 259) logged into the program materials once or twice, and 10.2% ( n = 85) of the whole s le engaged with the program actively, having logged in three or more times. The total number of student logins peaked in week 2, reduced between week 2 and week 7 and thereafter activity remained stable until the end of the semester. We hypothesise that the changes in wellbeing, stress and mindfulness at the end of the semester seen in the low engagement participants may partly be explained by the circumstances of COVID-19 restrictions improving. This study has revealed and discusses the complexities of student behaviour and implications for implementing an online mindfulness program in the real- world setting of a university.
Nanoparticle-mediated dual delivery of an antioxidant and a peptide against the L-Type Ca2+ channel enables simultaneous reduction of cardiac ischemia-reperfusion injury
Publisher: American Chemical Society (ACS)
Date: 22-12-2015
DOI: 10.1021/NN5061404
Abstract: Increased reactive oxygen species (ROS) production and elevated intracellular Ca(2+) following cardiac ischemia-reperfusion injury are key mediators of cell death and the development of cardiac hypertrophy. The L-type Ca(2+) channel is the main route for calcium influx in cardiac myocytes. Activation of the L-type Ca(2+) channel leads to a further increase in mitochondrial ROS production and metabolism. We have previously shown that the application of a peptide derived against the alpha-interacting domain of the L-type Ca(2+) channel (AID) decreases myocardial injury post reperfusion. Herein, we examine the efficacy of simultaneous delivery of the AID peptide in combination with the potent antioxidants curcumin or resveratrol using multifunctional poly(glycidyl methacrylate) (PGMA) nanoparticles. We highlight that drug loading and dissolution are important parameters that have to be taken into account when designing novel combinatorial therapies following cardiac ischemia-reperfusion injury. In the case of resveratrol low loading capacity and fast release rates hinder its applicability as an effective candidate for simultaneous therapy. However, in the case of curcumin, high loading capacity and sustained release rates enable its effective simultaneous delivery in combination with the AID peptide. Simultaneous delivery of the AID peptide with curcumin allowed for effective attenuation of the L-type Ca(2+) channel-activated increases in superoxide (assessed as changes in DHE fluorescence Empty NP = 53.1 ± 7.6% NP-C-AID = 7.32 ± 3.57%) and mitochondrial membrane potential (assessed as changes in JC-1 fluorescence Empty NP = 19.8 ± 2.8% NP-C-AID=13.05 ± 1.78%). We demonstrate in isolated rat hearts exposed to ischemia followed by reperfusion, that curcumin and the AID peptide in combination effectively reduce muscle damage, decrease oxidative stress and superoxide production in cardiac myocytes.
The cosmic assembly of stellar haloes in massive early-type Galaxies
Publisher: Oxford University Press (OUP)
Date: 09-01-2017
Evaluation of a biologically relevant level of MMW radiation absorption in neuronal tissue
Publisher: IEEE
Date: 08-2017
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