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

Previous studies have demonstrated that hydrogen sulfide (H ₂S) protects against multiple cardiovascular disease states in a similar manner as nitric oxide (NO). H ₂S therapy also has been shown to augment NO bioavailability and signaling. The purpose of this study was to investigate the impact of H ₂S deficiency on endothelial NO synthase (eNOS) function, NO production, and ischemia/reperfusion (I/R) injury. We found that mice lacking the H ₂S-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 ₂S therapy restored eNOS function and NO bioavailability and attenuated I/R injury. In addition, we found that H ₂S therapy fails to protect against I/R in eNOS phosphomutant mice (S1179A). Our results suggest that H ₂S-mediated cytoprotective signaling in the setting of I/R injury is dependent in large part on eNOS activation and NO generation.