Angiotensin II-Induced vascular remodeling and hypertension involves cathepsin L/V- MEK/ERK mediated mechanism
Angiotensin II-Induced vascular remodeling and hypertension involves cathepsin L/V- MEK/ERK mediated mechanism
复制标题
血管紧张素 II 诱导的血管重塑和高血压涉及组织蛋白酶 L/V-MEK/ERK 介导的机制
DOI：
10.1016/j.ijcard.2019.09.070
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发表时间：
2020-01-01
影响因子：
3.5
通讯作者：
Cai, Jingjing
中科院分区：
文献类型：
--
作者：
Lu, Yao;Sun, Xuejing;Cai, Jingjing
高血压的发展涉及广泛的动脉壁重塑，其中半胱氨酸蛋白酶发挥重要作用。据报道，组织蛋白酶L/V是一种半胱氨酸蛋白酶，与组织炎症反应和细胞外基质积累密切相关，使其能够调节动脉重塑。本研究旨在探讨组织蛋白酶L/V及其调控途径在高血压血管重构中的作用。我们发现，组织蛋白酶L/V及其内源性抑制剂胱抑素C，以及丝裂原活化蛋白激酶（MEK）磷酸化，在高血压患者的肠系膜动脉和血清中上调。使用血管紧张素II诱导的高血压模型，我们观察到主动脉中膜厚度，组织蛋白酶L活性，血压和MEK磷酸化的增加。用组织蛋白酶L抑制剂Z-FF-FMK或组织蛋白酶L基因缺失治疗显著减弱血管紧张素II诱导的高血压、动脉重塑、组织蛋白酶L激活和MEK磷酸化。此外，siRNA-组织蛋白酶V显着阻断血管紧张素II诱导的MEK和细胞外信号调节激酶（ERK）的磷酸化，但没有在人主动脉平滑肌细胞（HASMCs）的细胞增殖。进一步用ERK磷酸化抑制剂U 0126处理也阻断了血管紧张素II诱导的HASMCs增殖。结果表明，抑制组织蛋白酶L防止动脉重塑和高血压，部分通过抑制MEK-ERK信号介导的调节血管壁中的平滑肌细胞增殖。(C)2019年，任作家。由爱思唯尔公司出版
The development of hypertension involves extensive arterial wall remodeling, in which cysteine proteases play an essential role. Cathepsin L/V has been reported to be a cysteine protease that is closely intertwined with the tissue inflammatory response and extracellular matrix accumulation, allowing it to regulate arterial remodeling. The aim of this study was to determine the role of cathepsin L/V and its regulatory pathway in vascular remodeling in hypertension. We showed that cathepsin L/V and its endogenous inhibitor cystatin C, as well as mitogen-activated protein kinase (MEK) phosphorylation, were upregulated in the mesenteric arteries and serum of hypertensive patients. Using a model of angiotensin II-induced hypertension, we observed an increase in aortic artery media thickness, cathepsin L activity, blood pressure and MEK phosphorylation. Treatment with the cathepsin L inhibitor Z-FF-FMK or the genetic deletion of cathepsin L significantly attenuated angiotensin II-induced hypertension, arterial remodeling, cathepsin L activation and MEK phosphorylation. In addition, siRNA-cathepsin V significantly blocked angiotensin II-induced MEK and extracellular signal-regulated kinase (ERK) phosphorylation but not cell proliferation in human aortic smooth muscle cells (HASMCs). Further treatment with the ERK phosphorylation inhibitor U0126 also blocked angiotensin II-induced HASMCs proliferation. The results indicate that the inhibition of cathepsin L prevents arterial remodeling and hypertension, in part by inhibiting the MEK-ERK signaling-mediated regulation of smooth muscle cell proliferation in the vessel wall. (C) 2019 The Authors. Published by Elsevier B.V.