H ₂ S Protects Against Pressure Overload–Induced Heart Failure via Upregulation of Endothelial Nitric Oxide Synthase

Abstract

Introduction Cystathionine gamma-lyase (CSE) produces H2S via enzymatic conversion of L-cysteine and plays a critical role in cardiovascular homeostasis. We investigated the effects of genetic modulation of CSE and exogenous H2S therapy in the setting of pressure overload-induced heart failure. Methods and Results Transverse aortic constriction (TAC) was performed in wild-type (WT), CSE knockout (KO), and cardiac specific CSE transgenic (CS-CSE Tg) mice. In addition, C57BL/6J or CSE KO mice received a novel–H2S donor (SG-1002). Mice were followed for 12 weeks using echocardiography. We observed a >60% reduction in myocardial and circulating H2S levels following TAC. CSE KO mice exhibited cardiac dilatation and dysfunction significantly greater than WT mice following TAC and CS-CSE Tg mice maintained cardiac structure and function following TAC. H2S therapy with SG-1002 resulted in cardioprotection during TAC via upregulation of the VEGF-Akt-eNOS-nitric oxide-cGMP pathway with preserved mitochondrial function, attenuated oxidative stress, and increased myocardial vascular density. Conclusions Our results demonstrate that H2S levels are decreased in mice in the setting of heart failure. Moreover, CSE plays a critical role in the preservation of cardiac function in heart failure and oral H2S therapy prevents the transition from compensated to decompensated heart failure in part via upregulation of endothelial nitric oxide synthase (eNOS) and increased NO bioavailability.

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

“…It is well established that both H 2 S and NO exert potent cytoprotective effects in the setting of cardiovascular disease in various animal model systems (5,7,(13)(14)(15). In addition, H 2 S has been reported to be cytoprotective in some organ systems, such as the central nervous system and gastrointestinal tract, independent of NO (3,11,(16)(17)(18).…”

“…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).…”

“…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.…”

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

“…The interrelation of NO‐H 2 S and their biochemical interactions are complex and currently unclear. While some studies have shown that NO‐H 2 S positively affect each other's production and function,35, 51 other studies report contrarian, if not directly opposite findings 55, 56. Studies have shown that H 2 S has opposing effects on NOS/NO metabolism.…”

“…Under these conditions, the 3 gases have the ability to synergize their anti‐apoptotic, anti‐inflammatory, and antihypertrophic effects, which lead to cardioprotection. Although H 2 S and NO are thought to modulate independent pathways, there is evidence of cross‐talk between these 2 signaling molecules 35, 36. Our laboratory previously demonstrated that treatment with exogenous H 2 S or modulation of the endogenous production of H 2 S through the cardiac‐specific overexpression of the H 2 S‐generating enzyme CSE protects against acute MI/R injury and HF by attenuating oxidative stress, inhibiting apoptosis, and reducing inflammation 34, 37.…”