Hydrogen sulfide cytoprotective signaling is endothelial nitric oxide synthase-nitric oxide dependent

Abstract

Previous studies have demonstrated that hydrogen sulfide (H 2 S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H 2 S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H 2 S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H 2 S-producing enzyme cystathionine γ-lyase (CSE) exhibit elevated oxidative stress, dysfunctional eNOS, diminished NO levels, and exacerbated myocardial and hepatic I/R injury. In CSE KO mice, acute H 2 S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H 2 S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H 2 S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.eNOS uncoupling | myocardial infarction | cystathionase | Cth | nitrite H ydrogen sulfide (H 2 S), historically known for its odorous smell and toxicity at high concentrations, has recently been classified as a physiological signaling molecule with robust cytoprotective actions in multiple organ systems (1-3). H 2 S is produced enzymatically in mammalian tissues by three different enzymes: cystathionine γ-lyase (CSE), cystathionine beta-synthase (CBS), and 3-mercatopyruvate sulfurtransferase (3-MST). CSE, involved in the cysteine biosynthesis pathway, coordinates with L-cystine to produce H 2 S within the vasculature and is known to regulate blood pressure, modulate cellular metabolism, promote angiogenesis, regulate ion channels, and mitigate fibrosis and inflammation (4). Endothelial nitric oxide synthase (eNOS) catalyzes the production of nitric oxide (NO) from L-arginine within the endothelium to regulate vascular tone via cGMP signaling in vascular smooth muscle, mitochondrial respiration, platelet function, inflammation, and angiogenesis. The biological profiles of H 2 S and NO are similar, and both molecules are known to protect cells against various injurious states that result in organ injury. Although H 2 S and NO are thought to modulate independent signaling pathways, there is limited evidence of cross-talk between these two molecules (5, 6).H 2 S therapeutics and endogenous overexpression of CSE have been shown to attenuate ischemia/reperfusion (I/R) injury (7,8). Similarly, NO therapy and eNOS gene overexpression are also protective in ischemic disease states (9). Given the potent antioxidant actions of H 2 S (10, 11) and the effects of exogenous H 2 S therapy on NO bioavailability (5, 8), we investigated the effects of genetic deletion of the cystathionase gene (Cth, i.e., CSE KO) on the regulation of eNOS function and NO bioavailability. ResultsSulfide Levels are Reduced in CSE KO Mice. Whole blood and heart specimens were collected from WT and CSE KO mice to measure H 2 S levels using a high-sensitivity gas chromato...

Nitrite Therapy Ameliorates Myocardial Dysfunction via H 2 S and Nuclear Factor‐Erythroid 2‐Related Factor 2 (Nrf2)‐Dependent Signaling in Chronic Heart Failure

“…Our previous study indicated that H 2 S therapy increased nitrite levels and phosphorylation of eNOS Ser1177, resulting in cardioprotection in CSE KO mice and suggested significant cross‐talk between the H 2 S and NO signaling pathways 50. Therefore, we examined the hypothesis that nitrite therapy could also induce H 2 S production, contributing to the protection of cardiac function.…”

The role of hydrogen sulfide in diastolic function restoration during aging

“…* P <0.05 relative to adult animals (100%). # P <0.05 relative to old rats, which were not treated with NaHS and homogenate of the heart from old rats should be separately noted, as the latter serves as a regulator of NO synthesis and powerful cardio-and vasoprotector [7][8][9][10]. The injection of exogenic hydrogen sulfide donor, NaHS, significantly increased the amount of H 2 S both in the mitochondria and homogenate of the heart from old animals, which was accompanied by a significant inhibition of both oxidative and nitrosative stress.…”

“…Nowadays, there has been increasing evidence for cNOS uncoupling as the primary source of O 2 • -in the cells [5,6]. On the other hand, it was shown that hydrogen sulfide (H 2 S) has positive cardiovascular effect through cNOS stimulation [7,8].That stimulation could be a result of cNOS recoupling. Thus H 2 S can lead to cNOS coupling and improve the functional state of the cardiovascular system with aging.…”

“…This effect is due to antioxidant, anti-inflammatory properties of the gas, as well as its ability to regulate the constitutive de novo synthesis of NO [7][8][9][10].…”

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“…Особливої уваги потребує питання взаємодії H 2 S і NO. Згідно з останніми даними, H 2 S може збільшувати синтез NO як через фосфорилювання сNOS за PI3K/Akt-сигнальним механізмом, так і незалежно від нього [5,8]. Також відомо, що сірководень здатен пригнічувати фосфодіе-стеразу, фермент, що розщеплює цГМФ у клітині, і пролонгувати цим самим дію NO на ГМ [9][10][11].…”