S-Nitrosothiols and theS-Nitrosoproteome of the Cardiovascular System

Abstract

Significance: Since their discovery in the early 1990's, S-nitrosylated proteins have been increasingly recognized as important determinants of many biochemical processes. Specifically, S-nitrosothiols in the cardiovascular system exert many actions, including promoting vasodilation, inhibiting platelet aggregation, and regulating Ca 2+ channel function that influences myocyte contractility and electrophysiologic stability. Recent Advances: Contemporary developments in liquid chromatography-mass spectrometry methods, the development of biotin-and His-tag switch assays, and the availability of cyanide dye-labeling for S-nitrosothiol detection in vitro have increased significantly the identification of a number of cardiovascular protein targets of S-nitrosylation in vivo. Critical Issues: Recent analyses using modern S-nitrosothiol detection techniques have revealed the mechanistic significance of S-nitrosylation to the pathophysiology of numerous cardiovascular diseases, including essential hypertension, pulmonary hypertension, ischemic heart disease, stroke, and congestive heart failure, among others. Future Directions: Despite enhanced insight into S-nitrosothiol biochemistry, translating these advances into beneficial pharmacotherapies for patients with cardiovascular diseases remains a primary as-yet unmet goal for investigators within the field. Antioxid. Redox Signal. 18, 270-287.

Gastric S-nitrosothiol formation drives the antihypertensive effects of oral sodium nitrite and nitrate in a rat model of renovascular hypertension

“…However, this a very complex issue because S-nitrosothiols (perhaps Snitrosoglutathione) formed in the stomach (or gastric circulation) can trans-nitrosate a variety of proteins and modify their activity [27,47]. Indeed, protein nitros(yl)ation is now accepted as a major post-translational modification regulating cell biology, organ function, and drug responses [48][49][50][51]. It is astonishing that many critical protein targets for S-nitros(yl)ation are still unstudied, particularly in the context of oral administration of nitrite and nitrate, even though it is clear that highly nitros(yl)ating species are formed when nitrites are exposed to the acidic environment of the stomach [52].…”

Specificity in S-Nitrosylation: A Short-Range Mechanism for NO Signaling?

“…The nonclassical pathway is inherently related to NO-induced post-translational modifications of thiols, such as S-nitrosylation and S-glutathionylation (103,105,106). For a comprehensive update on the role of these PTMs in the cardiovascular system, the readers may wish to consult recent excellent reviews (102,138).…”

Antioxidants, inflammation and cardiovascular disease

“…S-nitrosylation of the proteome is a unique form of posttranslational modification that can have significant consequences for protein function and cell phenotype. In particular in the cardiovascular system, S-nitrosothiols were shown to exert many actions, including promoting vasodilation, inhibiting platelet aggregation, and regulating Ca(2+) channel function of myocytes [105] . The impact of S-nitroso but also N-nitroso protein formation on the reduction of free NO under inflammatory conditions in vivo has still to be investigated [106,107] .…”