Gaseous Signaling Molecules in Cardiovascular Function: From Mechanisms to Clinical Translation

Abstract

Carbon monoxide (CO), hydrogen sulfide (HS), and nitric oxide (NO) constitute endogenous gaseous molecules produced by specific enzymes. These gases are chemically simple, but exert multiple effects and act through shared molecular targets to control both physiology and pathophysiology in the cardiovascular system (CVS). The gases act via direct and/or indirect interactions with each other in proteins such as heme-containing enzymes, the mitochondrial respiratory complex, and ion channels, among others. Studies of the major impacts of CO, HS, and NO on the CVS have revealed their involvement in controlling blood pressure and in reducing cardiac reperfusion injuries, although their functional roles are not limited to these conditions. In this review, the basic aspects of CO, HS, and NO, including their production and effects on enzymes, mitochondrial respiration and biogenesis, and ion channels are briefly addressed to provide insight into their biology with respect to the CVS. Finally, potential therapeutic applications of CO, HS, and NO with the CVS are addressed, based on the use of exogenous donors and different types of delivery systems.

Hydrogen Sulfide as a Potential Alternative for the Treatment of Myocardial Fibrosis

“…Although the inhalation of H 2 S gas produces few byproducts, controlling its dosage and handling the specialized equipment needed for its delivery is difficult. There are a number of compounds that have been synthesized specifically to deliver therapeutic H 2 S to tissues [9,23,33], including inorganic sulfide salts (e.g., NaHS), synthetic organic compounds with a slow H 2 S-releasing mode, conventional drug molecules coupled with an H 2 S-donating group, cysteine analogs, nucleoside phosphorothioates, and plant-derived polysulfides (Table 1).…”

“…Level. The bioavailability of H 2 S inside the cell is primarily regulated by H 2 S-synthesizing enzymes (CSE, CBS, or 3-MST) and H 2 S-oxidizing enzymes located in the mitochondria (e.g., sulfide quinone reductase, persulfide dioxygenase, and thiosulfate sulfurtransferase) [9]. Cysteine and its derivatives can be used to boost H 2 S synthesis [33].…”

“…Despite its previous characterization as a toxic gas with a rotten egg smell, H 2 S is beginning to be associated with a growing family of gasotransmitters, with properties similar to nitric oxide (NO) and carbon monoxide (CO) [8][9][10]. As a gasotransmitter, H 2 S is involved in both the physiology and pathophysiology of the nervous, cardiovascular, and gastrointestinal systems via its antioxidant, anti-inflammatory [11], antinociceptive, antihypertensive, neuromodulative, and cytoprotective effects [9,[12][13][14]. The modulation of signals involved in myocardial fibrosis, and thereby the attenuation of pathological fibrosis, is an area of intense scientific interest due to its evident therapeutic implications for the treatment of HF [15].…”

“…H 2 S is not the sole gasotransmitter in the body and can interact with other gasotransmitters including NO and CO. In addition to direct chemical crosstalk, NO, CO, and H 2 S compete in heme-or metal-containing proteins and at the posttranslational modification sites of proteins [9]. Thus, various types of crosstalk between CO, H 2 S, and NO in the cardiovascular system exist [9].…”

“…In addition to direct chemical crosstalk, NO, CO, and H 2 S compete in heme-or metal-containing proteins and at the posttranslational modification sites of proteins [9]. Thus, various types of crosstalk between CO, H 2 S, and NO in the cardiovascular system exist [9]. For example, nitrosopersulfide, polysulfides, and dinitrososulfite can be formed by the interaction of NO and H 2 S. These anionic intermediates modulate the bioavailability of NO/HNO or H 2 S/sulfane sulfur and are thus responsible for distinct physiological consequences [22].…”