Regulation of cardiovascular cell function by hydrogen sulfide (H₂S)

Abstract

Since the discovery of endogenously-produced hydrogen sulfide (H 2 S) in various tissues, there has been an explosion of interest in H 2 S as a biological mediator alongside other gaseous mediators, nitric oxide and carbon monoxide. The identification of enzymeregulated H 2 S synthetic pathways in the cardiovascular system has led to a number of studies examining specific regulatory actions of H 2 S. We review evidence showing that endogenously-generated and exogenously-administered H 2 S exerts a wide range of actions in vascular and myocardial cells including vasodilator/vasoconstrictor effects via modification of the smooth muscle tone, induction of apoptosis and anti-proliferative responses in the smooth muscle cells, angiogenic actions, effects relevant to inflammation and shock, and cytoprotection in models of myocardial ischemia-reperfusion injury. Several molecular mechanisms of action of H 2 S have been described. These include interactions of H 2 S with NO, redox regulation of multiple signaling proteins and regulation of K ATP channel opening. The gaps in our current understanding of precise mechanisms, the absence of selective pharmacological tools and the limited availability of H 2 S measurement techniques for living tissues, leave many questions about physiological and pathophysiological roles of H 2 S unanswered at present. Nevertheless, this area of investigation is advancing rapidly. We believe H 2 S holds promise as an endogenous mediator controlling a wide range of cardiovascular cell functions and integrated responses under both physiological and pathological conditions and may be amenable to therapeutic manipulation.

Significance of Hydrogen Sulfide Production in the Pancreatic β-Cell

“…In early studies, H 2 S was found to facilitate the induction of hippocampal long-term potentiation by enhancing the activity of NMDA receptors in neurons (10). It also enhances NO-induced relaxation of vascular and intestinal smooth muscles (11) and inhibits high K + -induced corticotropine secretion from hypothalamic slices (12 (5,9,14). In contrast, exposure to H 2 S is reported to facilitate apoptotic cell death in aortic smooth muscle cells, lung fibroblasts, and pancreatic acinar cells (13).…”

“…H 2 S seems to contribute to the pathogenesis of several diseases, including Alzheimer's disease, hypertension, and cardiac infarction (4,9,32). Therefore, modulation of its production may be a potential therapeutic strategy for these diseases.…”

A Practical Look at the Chemistry and Biology of Hydrogen Sulfide

“…Excitement over this molecule, from basic research to translational medicine, has spawned nearly as many reviews as primary research articles (cf. 17,24,32,38,44,49,55,56,68,79). In many instances H 2 S seems to fit the criteria for a ''gasotransmitter'' as adapted from the wellknown criteria for neurotransmitters by Wang (74); i.e., gasotransmitters must 1) be a small molecule of gas, 2) be freely membrane permeable, 3) be endogenously and enzymatically generated in a regulated manner, 4) have well-defined specific functions at physiologically relevant concentrations, and 5) act on specific cellular targets.…”

Decreased Cystathionine-γ-lyase (CSE) Activity in Livers of Type 1 Diabetic Rats and Peripheral Blood Mononuclear Cells (PBMC) of Type 1 Diabetic Patients

“…The physiological importance of H 2 S is gaining acceptance with respect to its beneficial effects on various aspects of cardiovascular pathophysiology (1,2). Cell culture studies report that H 2 S supplementation can decrease oxidative stress and the secretion of proinflammatory cytokines, such as MCP-1 and IL-8, and activate insulin signaling pathways using monocytes (3), endothelial cells (4), and adipocytes (5).…”