Endothelial Cell Cystathionine γ-Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury

• Published in: Journal of the American Heart Association Vol. 9; no. 19; p. e017544
• Main Authors: Xia, Huijing, Li, Zhen, Sharp, 3rd, Thomas E, Polhemus, David J, Carnal, Jean, Moles, Karl H, Tao, Ya-Xiong, Elrod, John, Pfeilschifter, Josef, Beck, Karl-Friedrich, Lefer, David J
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 20.10.2020; Wiley
• Subjects: Animals; Aorta, Thoracic - metabolism; Aorta, Thoracic - physiopathology; cardioprotection; Cystathionine gamma-Lyase - metabolism; cystathionine γ‐lyase; Endothelial Cells - metabolism; endothelial function; Exercise Tolerance - physiology; hydrogen sulfide; Hydrogen Sulfide - metabolism; Mice; Mice, Transgenic; Myocardial Reperfusion Injury - metabolism; Myocardium - metabolism; Myocardium - pathology; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - metabolism; Original Research; Signal Transduction; endothelial function; cardioprotection; nitric oxide; hydrogen sulfide; cystathionine γ‐lyase
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.120.017544

Background Hydrogen sulfide (H S) is an important endogenous physiological signaling molecule and exerts protective properties in the cardiovascular system. Cystathionine γ-lyase (CSE), 1 of 3 H 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 H 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 H 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 H S production in endothelial cells is critical in maintaining endothelial function, exercise capacity, 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.