ORCID Profile
0000-0003-2651-4280
Current Organisation
University of Adelaide
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Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.IJCARD.2013.07.159
Abstract: Impaired tissue responsiveness to nitric oxide (NO) occurs in many cardiovascular diseases as well as with advanced age and is a correlate of poor outcomes. This phenomenon results from oxidative stress, with NO "scavenging" and dysfunction of soluble guanylate cyclase (sGC). Thioredoxin-interacting protein (TXNIP) is a major intracellular regulator of inflammatory activation and redox stress, but its interactions with NO/sGC are poorly understood. We have now evaluated the relationship between platelet TXNIP expression and function of the NO/sGC axis in subjects of varying age and during therapy with ramipril. Young (n=42) and aging (n=49) subjects underwent evaluation of platelet TXNIP content. Aging subjects additionally had measurements of platelet NO responsiveness and routine biochemistry. Platelet TXNIP content was greater (376±33 units) in the aging compared to younger subjects (289±13 units p<0.05). In the aging subjects there was a significant negative correlation (r=-0.50, p<0.001) between platelet TXNIP content and NO responsiveness. In a separate cohort of 15 subjects two week treatment with ramipril, which reversed platelet NO resistance and potentiated sGC activity, also decreased platelet TXNIP content by 40% (p=0.011). Platelet TXNIP content increases with aging, varies inversely with responsiveness to NO, and diminishes rapidly following treatment with ramipril. These data suggest that TXNIP-induced oxidative stress may be a critical modulator of tissue resistance to NO, a fundamental basis for cardiovascular disease. Analogously suppression of TXNIP expression can potentially be utilized as an index of restoration of cardiovascular homeostasis.
Publisher: Elsevier BV
Date: 02-2020
DOI: 10.1093/AJCN/NQZ317
Publisher: Elsevier BV
Date: 09-2012
DOI: 10.1016/J.JACC.2012.01.066
Abstract: Using 2 sequential studies in HOPE (Heart Outcomes Prevention Evaluation) study-type patients, the aims of this study were: 1) to test the hypothesis that ramipril improves platelet nitric oxide (NO) responsiveness: and 2) to explore biochemical and physiological effects of ramipril in a cohort selected on the basis of platelet NO resistance. Ramipril prevents cardiovascular events, but the bases for these effects remain uncertain. NO resistance at both the platelet and vascular levels is present in a substantial proportion of patients with diabetes or ischemic heart disease and is an independent risk factor for cardiovascular events. Study 1 was a double-blind, randomized comparison of ramipril (10 mg) with placebo in a cohort of patients (n = 119) with ischemic heart disease or diabetes plus additional coronary risk factor(s), in which effects on platelet responsiveness to NO were compared. Study 2 was a subsequent short-term evaluation of the effects of ramipril in a cohort of subjects (n = 19) with impaired platelet NO responsiveness in whom additional mechanistic data were sought. In study 1, ramipril therapy increased platelet responsiveness to NO relative to the extent of aggregation (p < 0.001), but this effect occurred primarily in patients with severely impaired baseline NO responsiveness (n = 41). In study 2, ramipril also improved platelet NO responsiveness (p < 0.01), and this improvement was correlated directly with increased NO-stimulated platelet generation of cyclic guanosine monophosphate (p < 0.02) but not with changes in plasma thrombospondin-1 levels. Ramipril ameliorates platelet NO resistance in HOPE study-type patients, with associated increases in soluble guanylate cyclase responsiveness to NO. This effect is likely to contribute to treatment benefit and define patients in whom ramipril therapy is particularly effective.
Publisher: Springer Science and Business Media LLC
Date: 27-08-2020
Publisher: Wiley
Date: 11-02-2015
DOI: 10.1002/EJHF.242
Abstract: The release of the B-type natriuretic peptide (BNP) is increased in heart failure (HF), a condition associated with oxidative stress. BNP is known to exert anti-inflammatory effects including suppression of neutrophil superoxide (O2(-)) release. However, BNP-based restoration of homeostasis in HF is inadequate, and the equivocal clinical benefit of a recombinant BNP, nesiritide, raises the possibility of attenuated response to BNP. We therefore tested the hypothesis that BNP-induced suppression of neutrophil O2(-) generation is impaired in patients with acute HF. We have recently characterized suppression of neutrophil O2(-) generation (PMA- or fMLP-stimulated neutrophil burst) by BNP as a measure of its physiological activity. In the present study, BNP response was compared in neutrophils of healthy subjects (n = 29) and HF patients (n = 45). Effects of BNP on fMLP-induced phosphorylation of the NAD(P)H oxidase subunit p47phox were also evaluated. In acute HF patients, the suppressing effect of BNP (1 µmol/L) on O2(-) generation was attenuated relative to that in healthy subjects (P < 0.05 for both PMA and fMLP). Analogously, BNP inhibited p47phox phosphorylation in healthy subjects but not in HF patients (P < 0.05). However, O2(-)-suppressing effects of the cell-permeable cGMP analogue (8-pCPT-cGMP) were preserved in acute HF. Conventional HF treatment for 5 weeks partially restored neutrophil BNP responsiveness (n = 25, P < 0.05), despite no significant decrease in plasma NT-proBNP levels. BNP inhibits neutrophil O2(-) generation by suppressing NAD(P)H oxidase assembly. This effect is impaired in acute HF patients, with partial recovery during treatment.
Publisher: Elsevier BV
Date: 2015
DOI: 10.1016/J.IJCARD.2014.10.137
Abstract: Clinical factors associated with thromboembolic risk in AF patients are well characterized and include new onset AF. Biochemically, AF is associated with inflammatory activation and impairment of nitric oxide (NO) signalling, which may also predispose to thromboembolism: the bases for variability in these anomalies have not been identified. We therefore sought to identify correlates of impaired platelet NO signalling in patients hospitalized with atrial fibrillation (AF), and to evaluate the impact of acuity of AF. 87 patients hospitalized with AF were evaluated. Platelet aggregation, and its inhibition by the NO donor sodium nitroprusside, was evaluated using whole blood impedance aggregometry. Correlates of impaired NO response were examined and repeated in a "validation" cohort of acute cardiac illnesses. Whilst clinical risk scores were not significantly correlated with integrity of NO signalling, new onset AF was associated with impaired NO response (6 ± 5% inhibition versus 25 ± 4% inhibition for chronic AF, p<0.01). New onset AF was a multivariate correlate (p<0.01) of impaired NO signalling, along with platelet ADP response (p<0.001), whereas the associated tachycardia was not. Platelet ADP response was predicted by elevation of plasma thrombospondin-1 concentrations (p<0.01). Validation cohort evaluations confirmed that acute AF was associated with significant (p<0.05) impairment of platelet NO response, and that neither acute heart failure nor acute coronary syndromes were associated with similar impairment. Recent onset of AF is associated with marked impairment of platelet NO response. These findings may contribute to thromboembolic risk in such patients.
Publisher: Springer Science and Business Media LLC
Date: 29-06-2016
DOI: 10.1007/S10557-016-6671-4
Abstract: Altered platelet physiology may contribute to the emergence of thrombosis in patients with many forms of cardiovascular disease. Excess platelet activation may reflect increased stimulation of pro-aggregatory pathways. There is, however, increasing evidence that excessive platelet response, due to impaired efficacy of anti-aggregatory autacoids such as nitric oxide (NO) and prostacyclin (PGI
Publisher: Springer Science and Business Media LLC
Date: 08-2014
DOI: 10.1007/S10557-014-6538-5
Abstract: The thioredoxin system, which consists of thioredoxin (Trx), nicotinamide adenine dinucleotide phosphate (NADPH) and thioredoxin reductase (TrxR), has emerged as a major anti-oxidant involved in the maintenance of cellular physiology and survival. Dysregulation in this system has been associated with metabolic, cardiovascular, and malignant disorders. Thioredoxin-interacting protein (TXNIP), also known as vitamin D-upregulated protein or thioredoxin-binding-protein-2, functions as a physiological inhibitor of Trx, and pathological suppression of Trx by TXNIP has been demonstrated in diabetes and cardiovascular diseases. Furthermore, TXNIP effects are partially Trx-independent these include direct activation of inflammation and inhibition of glucose uptake. Many of the effects of TXNIP are initiated by its dissociation from intra-nuclear binding with Trx or other SH-containing proteins: these effects include its migration to cytoplasm, modulating stress responses in mitochondria and endoplasmic reticulum, and also potentially activating apoptotic pathways. TXNIP also interacts with the nitric oxide (NO) signaling system, with apparent suppression of NO effect. TXNIP production is modulated by redox stress, glucose levels, hypoxia and several inflammatory activators. In recent studies, it has been shown that therapeutic agents including insulin, metformin, angiotensin converting enzyme inhibitors and calcium channel blockers reduce TXNIP expression, although it is uncertain to what extent TXNIP suppression contributes to their clinical efficacy. This review addresses the role of TXNIP in health and in cardiovascular and metabolic disorders. Finally, the potential advantages (and disadvantages) of pharmacological suppression of TXNIP in cardiovascular disease and diabetes are summarized.
Publisher: Georg Thieme Verlag KG
Date: 31-08-2014
Abstract: The nitric oxide (NO)/soluble guanylate cyclase (sGC) system is fundamental to endothelial control of vascular tone, but also plays a major role in the negative modulation of platelet aggregation. The phenomenon of platelet NO resistance, or decreased antiaggregatory response to NO, occurs increasingly with advanced age, as well as in the context of cardiovascular disease states such as heart failure, ischemic heart disease, and aortic valve disease. The central causes of NO resistance are "scavenging" of NO and dysfunction of sGC. In the current review, we discuss the roles of several modulators of NO synthesis and of the NO/sGC cascade on changes in platelet physiology with aging, together with potential therapeutic options to reduce associated thrombotic risk.
Publisher: Springer Science and Business Media LLC
Date: 02-07-2015
DOI: 10.1007/S00059-015-4335-Y
Abstract: Atrial fibrillation (AF) is a condition where platelet hyperaggregability is commonly present. We examined potential physiological bases for platelet hyperaggregability in a cohort of patients with acute and chronic AF. In particular, we sought to identify the impact of inflammation [myeloperoxidase (MPO) and C-reactive protein (CRP)] and impaired nitric oxide (NO) signaling. Clinical and biochemical determinants of adenosine diphosphate (ADP)-induced platelet aggregation were sought in patients (n = 106) hospitalized with AF via univariate and multivariate analysis. Hyper-responsiveness of platelets to ADP was directly (r = 0.254, p < 0.01) correlated with plasma concentrations of thrombospondin-1 (TSP-1), a matricellular protein that impairs NO responses and contributes to development of oxidative stress. In turn, plasma TSP-1 concentrations were directly correlated with MPO concentrations (r = 0.221, p < 0.05), while MPO concentrations correlated with those of asymmetric dimethylarginine (ADMA, r = 0.220, p < 0.05), and its structural isomer symmetric dimethylarginine (SDMA, r = 0.192, p = 0.05). Multivariate analysis identified TSP-1 (β = 0.276, p < 0.05) concentrations, as well as female sex (β = 0.199, p < 0.05), as direct correlates of platelet aggregability, and SDMA concentrations (β = - 0.292, p < 0.05) as an inverse correlate. We conclude that platelet hyperaggregability, where present in the context of AF, may be engendered by impaired availability of NO, as well as via MPO-related inflammatory activation.
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.HRTHM.2015.12.010
Abstract: Atrial fibrillation (AF) is a condition that confers increased thromboembolic risk. Oral anticoagulant (OAC) therapy can attenuate this risk. However, use of OAC therapy is determined largely by the presence of additional clinical factors (encapsulated by the CHA2DS2VASc score) that incrementally elevate stroke risk. Currently, there is no specific recommendation regarding urgency of initiation of OAC therapy in the presence of new-onset AF, except where cardioversion is being considered. Recently, it has become increasingly apparent that there is a period immediately following the onset of AF of particularly accentuated thromboembolic risk (with respect to chronic AF): the physiological bases for this risk are as yet incompletely understood. However, given that both inflammation and impaired nitric oxide signaling are pivotally involved in the pathogenesis of AF, these factors may also mediate thrombotic risk in the context of new-onset AF. Advances in OAC therapy have recently been achieved, with development of agents that are comparable or superior to warfarin for mitigation of stroke risk, but with a safety profile similar to aspirin therapy. Thus, the incremental increase in thromboembolic risk experienced by new-onset AF patients constitutes a previously widely neglected case in favor of the rapid application of OAC therapy to such in iduals. This review seeks to summarize the thromboembolic risk observed in new-onset AF and the emerging understanding of the physiological bases for this risk.
Publisher: Hindawi Limited
Date: 2016
DOI: 10.1155/2016/9754808
Abstract: It has been documented recently that left atrial (LA) deformation in AF patients (while in AF) is predictive of subsequent stroke risk. Additionally, diminished LA deformation during AF correlates with the presence of LA blood stasis. Given that endothelial function is dependent on laminar blood flow, the present study sought to investigate the effect of diminished LA deformation (during AF) on platelet reactivity and inflammation in AF patients. Patients ( n = 17 ) hospitalised with AF underwent echocardiography (while in AF) for determination of peak positive LA strain (LASp). Whole blood impedance aggregometry was used to measure extent of ADP-induced aggregation and subsequent inhibitory response to the nitric oxide (NO) donor, sodium nitroprusside. Platelet thioredoxin-interacting protein (Txnip) content was determined by immunohistochemistry. LASp tended ( p = 0.078 ) to vary inversely with CHA 2 DS 2 VASc scores. However, mediators of inflammation (C-reactive protein, Txnip) did not correlate significantly with LASp nor did extent of ADP-induced platelet aggregation or platelet NO response. These results suggest that the thrombogenic risk associated with LA stasis is independent of secondary effects on platelet aggregability or inflammation.
Publisher: Wiley
Date: 14-03-2019
Publisher: Wiley
Date: 13-10-2018
DOI: 10.1002/EHF2.12211
No related grants have been discovered for Nathan Procter.