TY - JOUR
T1 - Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction
AU - Kassan, Modar
AU - Ait-Aissa, Karima
AU - Radwan, Eman
AU - Mali, Vishal
AU - Haddox, Samuel
AU - Gabani, Mohanad
AU - Zhang, Wei
AU - Belmadani, Souad
AU - Irani, Kaikobad
AU - Trebak, Mohamed
AU - Matrougui, Khalid
N1 - Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/9/1
Y1 - 2016/9/1
N2 - 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 (Stim1SMC-/-). 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-β 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 Stim1SMC-/- 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.
AB - 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 (Stim1SMC-/-). 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-β 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 Stim1SMC-/- 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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U2 - 10.1161/ATVBAHA.116.307869
DO - 10.1161/ATVBAHA.116.307869
M3 - Article
C2 - 27470514
AN - SCOPUS:84983782668
SN - 1079-5642
VL - 36
SP - 1900
EP - 1909
JO - Arteriosclerosis, thrombosis, and vascular biology
JF - Arteriosclerosis, thrombosis, and vascular biology
IS - 9
ER -