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

Physiological concentrations of hydrogen sulfide (H₂S) exert potent prosurvival actions. We demonstrate that the cytoprotective actions of H₂S are mediated in part via a second gaseous signaling molecule, nitric oxide (NO). We found that cystathionine γ-lyase (CSE) KO mice with reduced H₂S levels exhibit increased oxidative stress and an exacerbated response to myocardial ischemia/reperfusion injury. CSE KO mice also exhibit reduced levels of NO and reduced NO synthesis via endothelial NO synthase (eNOS). Both oxidative stress and myocardial injury in CSE KO mice were attenuated by exogenous H₂S therapy, with increased eNOS function and restoration of NO levels. These findings provide insight into H₂S-mediated cytoprotetion and important information regarding the translation of H₂S therapy to the clinic.