Endothelial cell cystathionine γ-lyase expression level modulates exercise capacity, vascular function, and myocardial ischemia reperfusion injury

Abstract

BACKGROUND: Hydrogen sulfide (H2 S) is an important endogenous physiological signaling molecule and exerts protective prop-erties in the cardiovascular system. Cystathionine γ-lyase (CSE), 1 of 3 H2 S producing enzyme, is predominantly localized in the vascular endothelium. However, the regulation of CSE in vascular endothelium remains incompletely understood. METHODS AND RESULTS: We generated inducible endothelial cell-specific CSE overexpressed transgenic mice (EC-CSE Tg) and endothelial cell-specific CSE knockout mice (EC-CSE KO), and investigated vascular function in isolated thoracic aorta, treadmill exercise capacity, and myocardial injury following ischemia-reperfusion in these mice. Overexpression of CSE in endothelial cells resulted in increased circulating and myocardial H2 S and NO, augmented endothelial-dependent vasorelaxation response in thoracic aorta, improved exercise capacity, and reduced myocardial-reperfusion injury. In contrast, genetic deletion of CSE in endothelial cells led to decreased circulating H2 S and cardiac NO production, impaired endothelial dependent vasorelaxation response and reduced exercise capacity. However, myocardial-reperfusion injury was not affected by genetic deletion of endothelial cell CSE. CONCLUSIONS: CSE-derived H2 S production in endothelial cells is critical in maintaining endothelial function, exercise capac-ity, and protecting against myocardial ischemia/reperfusion injury. Our data suggest that the endothelial NO synthase—NO pathway is likely involved in the beneficial effects of overexpression of CSE in the endothelium.