Endothelial Cell Cystathionine γ-Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury.
Endothelial Cell Cystathionine γ-Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury.
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DOI：
10.1161/jaha.120.017544
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发表时间：
2020-10-20
影响因子：
5.4
通讯作者：
Lefer DJ
中科院分区：
文献类型：
--
作者：
Xia H;Li Z;Sharp TE 3rd;Polhemus DJ;Carnal J;Moles KH;Tao YX;Elrod J;Pfeilschifter J;Beck KF;Lefer DJ
硫化氢(H_2S)是一种重要的内源性生理信号分子，在心血管系统中具有保护作用。胱硫醚裂解酶(Cystathionineγ-lyase，CSE)是3种硫化氢产生酶中的一种，主要定位于血管内皮细胞。然而，CSE对血管内皮细胞的调节仍不完全清楚。我们建立了可诱导的内皮细胞特异性CSE过表达转基因小鼠(EC-CSE TG)和内皮细胞特异性CSE基因敲除小鼠(EC-CSE KO)，并研究了这些小鼠的离体胸主动脉血管功能、跑台运动能力和缺血再灌注后的心肌损伤。CSE在血管内皮细胞中过表达可增加循环和心肌组织中的硫化氢和一氧化氮，增强胸主动脉内皮细胞依赖性的血管松弛反应，提高运动能力，减轻心肌再灌注损伤。相反，内皮细胞CSE基因缺失导致循环中硫化氢和心脏NO生成减少，内皮依赖性血管松弛反应受损，运动能力降低。然而，内皮细胞CSE基因缺失不影响心肌再灌注损伤。CSE在内皮细胞中产生的硫化氢在维持内皮功能、运动能力和保护心肌缺血/再灌注损伤中起着至关重要的作用。我们的数据提示，内皮细胞一氧化氮合酶-一氧化氮途径可能参与了CSE在内皮细胞过度表达的有利作用。
Hydrogen sulfide (H2S) is an important endogenous physiological signaling molecule and exerts protective properties in the cardiovascular system. Cystathionine γ‐lyase (CSE), 1 of 3 H2S producing enzyme, is predominantly localized in the vascular endothelium. However, the regulation of CSE in vascular endothelium remains incompletely understood. 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 H2S 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 H2S 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. CSE‐derived H2S 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.