Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure
Hydrogen Sulfide Modulates Endothelial-Mesenchymal Transition in Heart Failure
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DOI：
10.1161/circresaha.122.321326
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发表时间：
2023-01-20
影响因子：
20.1
通讯作者：
Lefer, David J.
中科院分区：
文献类型：
--
作者：
Li, Zhen;Xia, Huijing;Lefer, David J.
背景：硫化氢是一种重要的内源性信号分子，在心力衰竭的情况下发挥保护作用。胱硫醚γ-裂解酶（CSE）是三种硫化氢产生酶之一，主要定位于血管内皮。内皮CSE-硫化氢轴和内皮-间质转化之间的相互作用，一个重要的病理过程，有助于纤维化的形成，还有待研究。方法：对内皮细胞特异性CSE敲除和内皮细胞CSE过表达小鼠进行横向主动脉缩窄以诱导射血分数降低的心力衰竭。测量心功能、血管反应性和平板运动能力，以确定心力衰竭的严重程度。进行组织学和基因表达分析以研究心脏纤维化和内皮-间质转化的活化的变化。结果：内皮细胞特异性CSE基因敲除小鼠表现出增加的内皮-间充质转化和降低的心肌一氧化氮生物利用度，这与心脏纤维化增加，心脏和血管功能受损以及运动能力恶化有关。相反，内皮细胞中CSE的基因过表达导致心肌一氧化氮增加，内皮间质转化和心脏纤维化减少，心脏和内皮功能得到保护，运动能力得到改善。结论：我们的数据表明，内皮CSE调节内皮间质转化，并改善压力超负荷诱导的心力衰竭的严重程度，部分通过一氧化氮相关机制。这些数据进一步表明，内皮源性硫化氢是治疗射血分数降低的心力衰竭的潜在治疗剂。
Background:Hydrogen sulfide is a critical endogenous signaling molecule that exerts protective effects in the setting of heart failure. Cystathionine gamma-lyase (CSE), 1 of 3 hydrogen-sulfide-producing enzyme, is predominantly localized in the vascular endothelium. The interaction between the endothelial CSE-hydrogen sulfide axis and endothelial-mesenchymal transition, an important pathological process contributing to the formation of fibrosis, has yet to be investigated. Methods:Endothelial-cell-specific CSE knockout and Endothelial cell-CSE overexpressing mice were subjected to transverse aortic constriction to induce heart failure with reduced ejection fraction. Cardiac function, vascular reactivity, and treadmill exercise capacity were measured to determine the severity of heart failure. Histological and gene expression analyses were performed to investigate changes in cardiac fibrosis and the activation of endothelial-mesenchymal transition. Results:Endothelial-cell-specific CSE knockout mice exhibited increased endothelial-mesenchymal transition and reduced nitric oxide bioavailability in the myocardium, which was associated with increased cardiac fibrosis, impaired cardiac and vascular function, and worsened exercise performance. In contrast, genetic overexpression of CSE in endothelial cells led to increased myocardial nitric oxide, decreased endothelial-mesenchymal transition and cardiac fibrosis, preserved cardiac and endothelial function, and improved exercise capacity. Conclusions:Our data demonstrate that endothelial CSE modulates endothelial-mesenchymal transition and ameliorate the severity of pressure-overload-induced heart failure, in part, through nitric oxide-related mechanisms. These data further suggest that endothelium-derived hydrogen sulfide is a potential therapeutic for the treatment of heart failure with reduced ejection fraction.