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.

Significance: An abundance of experimental evidence suggests that hydrogen sulfide (H 2 S) plays a prominent role in physiology and pathophysiology. Many targets exist for H 2 S therapy. The molecular targets of H 2 S include proteins, enzymes, transcription factors, and membrane ion channels. Recent Advances: Novel H 2 S precursors are being synthesized and discovered that are capable of releasing H 2 S in a slow and sustained manner. This presents a novel and advantageous approach to H 2

SummaryRecent studies demonstrate robust molecular cross talk and signaling between hydrogen sulfide (H2S) and nitric oxide (NO). Heart failure (HF) patients are deficient in both H2S and NO, two molecules that are critical for cardiovascular homeostasis. A phase I clinical trial of a novel H2S prodrug (SG1002) was designed to assess safety and changes in H2S and NO bioavailability in healthy and HF subjects. Healthy subjects (n = 7) and heart failure patients (n = 8) received oral SG1002 treatment in escalating dosages of 200, 400, and 800 mg twice daily for 7 days for each dose. Safety and tolerability were assessed by physical examination, vital signs, and ECG analysis. Plasma samples were collected during a 24‐h period each week for H2S and NO analysis. BNP and glutathione levels were analyzed as markers of cardiac health and redox status. Administration of SG1002 resulted in increased H2S levels in healthy subjects. We also observed increased H2S levels in HF subjects following 400 mg SG1002. Nitrite, a metabolite of NO, was increased in both healthy and HF patients receiving 400 mg and 800 mg SG1002. HF subjects treated with SG1002 displayed stable drug levels over the course of the trial. SG1002 was safe and well tolerated at all doses in both healthy and HF subjects. These data suggest that SG1002 increases blood H2S levels and circulating NO bioavailability. The finding that SG1002 attenuates increases in BNP in HF patients suggests that this novel agent warrants further study in a larger clinical study.

The COVID-19 pandemic caused by SARS-Cov-2 demands rapid, safe and effective therapeutic options. In the last decades, the endogenous gasotransmitter hydrogen sulfide (H 2 S) has emerged as modulator of several biological functions and its deficiency has been associated with different disorders. Therefore, many H 2 S-releasing agents have been developed as potential therapeutic tools for diseases related with impaired H 2 S production and/or activity. Some of these compounds are in advanced clinical trials. Presently, the pivotal role of H 2 S in modulating the inflammatory response and pro-inflammatory cytokine cascade is well recognized, and the usefulness of some H 2 S-donors for the treatment of acute lung inflammation has been reported. Recent data is elucidating several mechanisms of action, which may account for antiviral effects of H 2 S. Noteworthy, some preliminary clinical results suggest an inverse relationship between endogenous H 2 S levels and severity of COVID-19. Therefore, repurposing of H 2 S-releasing drugs may be a potential therapeutic opportunity for treatment of COVID-19.

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