The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness

Dautov, Rustem; Ngo, D.; Licari, Giovanni; Liu, S.; Sverdlov, Aaron L.; Ritchie, Rebecca H; Kemp-Harper, Barbara K; Horowitz, John D.; Chirkov, Yuliy Y.

doi:10.1016/j.niox.2013.08.006

Cited by 23 publications

(22 citation statements)

References 49 publications

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“…10 Exogenously applied HNO confers vasoprotective effects, 11 increases heart muscle contractility, 12 and inhibits platelet aggregation. 13 HNO also exacerbates ischemia-related injury 14 and induces neurotoxicity. 15 Under biological conditions, HNO is both an electrophile that oxidizes thiols and a nucleophile that can coordinate and reduce metal ions.…”

Section: Introductionmentioning

confidence: 99%

A Fast and Selective Near-Infrared Fluorescent Sensor for Multicolor Imaging of Biological Nitroxyl (HNO)

et al. 2014

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The first near-infrared fluorescent turn-on sensor for the detection of nitroxyl (HNO), the one-electron reduced form of nitric oxide (NO), is reported. The new copper-based probe, CuDHX1, contains a dihydroxanthene (DHX) fluorophore and a cyclam derivative as a Cu(II) binding site. Upon reaction with HNO, CuDHX1 displays a five-fold fluorescence turn-on in cuvettes and is selective for HNO over thiols and reactive nitrogen and oxygen species. CuDHX1 can detect exogenously applied HNO in live mammalian cells and in conjunction with the zinc-specific, green-fluorescent sensor ZP1 can perform multicolor/multianalyte microscopic imaging. These studies reveal that HNO treatment elicits an increase in the concentration of intracellular mobile zinc.

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Section: Introductionmentioning

confidence: 99%

A Fast and Selective Near-Infrared Fluorescent Sensor for Multicolor Imaging of Biological Nitroxyl (HNO)

et al. 2014

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“…NO• resistance occurs largely due to oxidative stress, where ROS scavenge NO• and reversibly inactivate sGC, resulting in impaired tissue responsiveness to endogenous or exogenous NO• (Dautov et al, 2013;Tare et al, 2017). Oxidative stress refers to an imbalance between the generation of ROS and their clearance by endogenous antioxidants, such as superoxide dismutase, catalase and glutathione peroxidase (Wink et al, 2001).…”

Section: Oxidative Stress As a Contributor To Nitric Oxide Resistancementioning

confidence: 99%

“…•Can cause hypotension (Follmann et al, 2013;Buys et al, 2018;Elgert et al, 2019) Nitrite (Dautov et al, 2013;Siddiqi et al, 2014;Jones et al, 2015) Nitroxyl donors •Vasodilator, anti-aggregatory, positive cardiac inotropic/lusitropic actions •sGC-dependent & -independent signaling •Resistant to oxidative stress…”

Section: Nitritementioning

confidence: 99%

“…NO• resistance affects multiple sites in the cardiovascular system, including the myocardium, vasculature and platelets (Qin et al, 2020). As such, patients with diabetes fail to respond to the anti-aggregatory and vasodilator effects of NO•-based pharmacotherapies during cardiovascular emergencies, such as acute myocardial infarction, transient myocardial ischemia and acute decompensated heart failure (Dautov et al, 2013). Several pharmacotherapies including statins, some angiotensin-converting enzyme (ACE) inhibitors, perhexiline, and insulin (in the presence of severe hyperglycemia) ameliorate NO• resistance (Chirkov and Horowitz, 2007), while sGC activators primarily circumvent the problem (Costell et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling

et al. 2020

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Diabetes is associated with an increased mortality risk due to cardiovascular complications. Hyperglycemia-induced oxidative stress underlies these complications, leading to an impairment in endogenous nitric oxide (NO•) generation, together with reductions in NO• bioavailability and NO• responsiveness in the vasculature, platelets and myocardium. The latter impairment of responsiveness to NO•, termed NO• resistance, compromises the ability of traditional NO•-based therapeutics to improve hemodynamic status during diabetes-associated cardiovascular emergencies, such as acute myocardial infarction. Whilst a number of agents can ameliorate (e.g. angiotensin converting enzyme [ACE] inhibitors, perhexiline, statins and insulin) or circumvent (e.g. nitrite and sGC activators) NO• resistance, nitroxyl (HNO) donors offer a novel opportunity to circumvent NO• resistance in diabetes. With a suite of vasoprotective properties and an ability to enhance cardiac inotropic and lusitropic responses, coupled with preserved efficacy in the setting of oxidative stress, HNO donors have intact therapeutic potential in the face of diminished NO• signaling. This review explores the major mechanisms by which hyperglycemia-induced oxidative stress drives NO• resistance, and the therapeutic potential of HNO donors to circumvent this to treat cardiovascular complications in type 2 diabetes mellitus.

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“…121,122 We have recently demonstrated that the HNO donor isopropylamine NONOate exerts potent antiaggregatory effects which are minimally impaired under conditions of NO resistance. 123 The therapeutic potential of HNO donors in acute thrombotic disorders is therefore considerable.…”

Section: Alternative Activators Of Soluble Guanylate Cyclasementioning

confidence: 99%

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

Procter

Chong

Sverdlov

et al. 2014

Semin Thromb Hemost

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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.

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The nitric oxide redox sibling nitroxyl partially circumvents impairment of platelet nitric oxide responsiveness

Cited by 23 publications

References 49 publications

A Fast and Selective Near-Infrared Fluorescent Sensor for Multicolor Imaging of Biological Nitroxyl (HNO)

A Fast and Selective Near-Infrared Fluorescent Sensor for Multicolor Imaging of Biological Nitroxyl (HNO)

Nitroxyl: A Novel Strategy to Circumvent Diabetes Associated Impairments in Nitric Oxide Signaling

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

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