Aging of Platelet Nitric Oxide Signaling: Pathogenesis, Clinical Implications, and Therapeutics

Procter, Nathan E.K.; Chong, Cher‐Rin; Sverdlov, Aaron L.; Chan, Wai Ping Alicia; Chirkov, Yuliy Y.; Horowitz, John D.

doi:10.1055/s-0034-1389082

Cited by 14 publications

(14 citation statements)

References 104 publications

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“…Increased ADP-induced platelet aggregation, plasma ADMA concentrations, as well as reductions in platelet NO responsiveness have been associated with aging [46, 47]. Deterioration in platelet NO responsiveness and increases in ADMA concentrations correlate with aging.…”

Section: Effect Of Adma and No On Cardiovascular Agingmentioning

confidence: 99%

Oxidative Stress and Cardiovascular Aging: Interaction Between NRF-2 and ADMA

Nair

Góngora

2017

CCR

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Background:The concept of antioxidant therapies assumes high importance as oxidative stress is associated with cardiovascular aging via endothelial dysfunction. This review focuses on exploring the interaction between nrf-2 and ADMA in influencing the nitric oxide pathway and cardiovascular function.Objective:A systematic review of literature from 1990 to 2016 was conducted using Pubmed and Google Scholar. The literature suggests a strong influence of nrf-2 activation on up regulation of DDAH I which degrades ADMA, the endogenous inhibitor of nitric oxide synthase. The resulting decrease of ADMA would in turn enhance nitric oxide (NO) production. This would support endothelial function by adequate NO production and homeostasis of endothelial function. Conclusion:As NO production has many positive pleiotropic effects in the cardiovascular system, such an interaction could be utilized for designing molecular therapeutics. The targets for therapy need not be limited to activation of nrf-2. Modulation of molecules downstream such as DDAH I can be used to regulate ADMA levels. Most current literature is supported by animal studies. The concept of antioxidant therapies needs to be tested in well-defined randomized control trials. The biochemical basis of nrf-2 activation needs to be substantiated in human studies.

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Section: Effect Of Adma and No On Cardiovascular Agingmentioning

confidence: 99%

Oxidative Stress and Cardiovascular Aging: Interaction Between NRF-2 and ADMA

Nair

Góngora

2017

CCR

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“…One of the factors contributing to platelet hyperaggregability in this context is potential impairment of the NO signaling pathway (see [ 26 ] for review). Effective generation of NO by endothelial NO synthase is impaired by the presence of nonlaminar blood flow, such as what occurs in the presence of AF [ 11 , 27 , 28 ].…”

Section: Discussionmentioning

confidence: 99%

Platelet Reactivity Is Independent of Left Atrial Wall Deformation in Patients with Atrial Fibrillation

Procter

Goh

Mahadevan

et al. 2016

Mediators of Inflammation

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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 CHA2DS2VASc 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.

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“…NO, that is predominantly generated from arginine via NO synthases, diffuses across cellular membranes and activates the NO "receptor" soluble guanylate cyclase (sGC). The resultant generation of 3′5′-cyclic guanosine monophosphate (cGMP), in turn, induces phosphorylation of the vasodilatorstimulated phosphoprotein (VASP) and the inhibition of platelet aggregation [4]. PGI 2 is generated indirectly from arachidonic acid and indirectly activates platelet adenylate cyclase (AC).…”

Section: Introductionmentioning

confidence: 99%

Impairment of Anti-Aggregatory Responses to Nitric Oxide and Prostacyclin: Mechanisms and Clinical Implications in Cardiovascular Disease

Chirkov

Nguyen

Horowitz

2022

IJMS

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The propensity towards platelet-rich thrombus formation increases substantially during normal ageing, and this trend is mediated by decreases in platelet responsiveness to the anti-aggregatory nitric oxide (NO) and prostacyclin (PGI2) pathways. The impairment of soluble guanylate cyclase and adenylate cyclase-based signalling that is associated with oxidative stress represents the major mechanism of this loss of anti-aggregatory reactivity. Platelet desensitization to these autacoids represents an adverse prognostic marker in patients with ischemic heart disease and may contribute to increased thrombo-embolic risk in patients with heart failure. Patients with platelet resistance to PGI2 also are unresponsive to ADP receptor antagonist therapy. Apart from ischemia, diabetes and aortic valve disease are also associated with impaired anti-aggregatory homeostasis. This review examines the association of impaired platelet cyclic nucleotide (i.e., cGMP and cAMP) signalling with the emerging evidence of thromboembolic risk in cardiovascular diseases, and discusses the potential therapeutic strategies targeting this abnormality.

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Aging of Platelet Nitric Oxide Signaling: Pathogenesis, Clinical Implications, and Therapeutics

Cited by 14 publications

References 104 publications

Oxidative Stress and Cardiovascular Aging: Interaction Between NRF-2 and ADMA

Oxidative Stress and Cardiovascular Aging: Interaction Between NRF-2 and ADMA

Platelet Reactivity Is Independent of Left Atrial Wall Deformation in Patients with Atrial Fibrillation

Impairment of Anti-Aggregatory Responses to Nitric Oxide and Prostacyclin: Mechanisms and Clinical Implications in Cardiovascular Disease

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