期刊
INTERNATIONAL JOURNAL OF CARDIOLOGY
卷 298, 期 -, 页码 98-106出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.ijcard.2019.09.070
关键词
Vascular remodeling; Angiotensin II; Hypertension; Cathepsin L/V; Mitogen-activated protein kinase (MAPK)
资金
- National Natural Science Foundation of China [81570271, 81870171, 81570451, 81800393, 81770403]
- National Key Research and Development Projects [2016YFC0900802]
- Major Science and Technology Project of Hunan Province [2016SK1001]
- Hunan Distinguished Young Scholars [2017RS3015]
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.
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