Essential Role Of Smooth Muscle Stim1 In Hypertension And Cardiovascular Dysfunction
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY(2016)
摘要
Objectives Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke.Approach and Results Here we show that wild-type mice infused with angiotensin II develop hypertension, cardiac hypertrophy, perivascular fibrosis, and endothelial dysfunction with enhanced stromal interaction molecule 1 (STIM1) expression in heart and vessels. All these pathologies were significantly blunted in mice lacking STIM1 specifically in smooth muscle (Stim1(SMC-/-)). Mechanistically, STIM1 upregulation during angiotensin II-induced hypertension was associated with enhanced endoplasmic reticulum stress, and smooth muscle STIM1 was required for endoplasmic reticulum stress-induced vascular dysfunction through transforming growth factor- and nicotinamide adenine dinucleotide phosphate oxidase-dependent pathways. Accordingly, knockout mice for the endoplasmic reticulum stress proapoptotic transcriptional factor, CCAAT-enhancer-binding protein homologous protein (CHOP-/-), were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with angiotensin II, but not Stim1(SMC-/-) or CHOP-/- mice showed elevated vascular nicotinamide adenine dinucleotide phosphate oxidase activity and reduced phosphorylated endothelial nitric oxide synthase, cGMP, and nitrite levels.Conclusions Thus, smooth muscle STIM1 plays a crucial role in the development of hypertension and associated cardiovascular pathologies and represents a promising target for cardiovascular therapy.
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关键词
cardiac hypertrophy,endothelial nitric oxide synthase,ER stress,hypertension,nicotinamide adenine dinucleotide phosphate,stromal interaction molecule 1,vascular reactivity
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