Abstract
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.
Highlights
Over 460 million individuals have diabetes, and this figure is projected to increase to 700 million by the year 2045 (Saeedi et al, 2019)
Nitroxyl (HNO) donors circumvent NO resistance and promote vasodilation, while uniquely inducing positive inotropic and lusitropic responses that persist in conditions of oxidative stress where responses to NO are diminished (Paolocci et al, 2003; Chin et al, 2016; Tare et al, 2017; Qin et al, 2020)
The aforementioned cardiovascular changes are associated with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), due to the prevalence of the latter, this review will explore the major mechanisms that drive impairments in NO signaling in T2DM, and highlight the therapeutic potential of HNO donors to circumvent this problem, in order to alleviate acute hemodynamic complications in T2DM
Summary
Over 460 million individuals have diabetes, and this figure is projected to increase to 700 million by the year 2045 (Saeedi et al, 2019). Decreased GAPDH activity leads to overactivation of the hexosamine pathway, upregulation of protein kinase C (PKC), elevated glucose flux through the polyol pathway and increased formation of advanced glycation end-products (AGEs), all of which can promote impairments in NO generation and/or signaling (Fiorentino et al, 2013) (Figure 2). Such protective actions of insulin are likely due to its ability to reduce oxidative stress, independently of the potential for acute modulation of platelet TXNIP expression (Chong et al, 2015).
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