Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction

Modar Kassan, Karima Ait-Aissa, Eman Radwan, Vishal Mali, Samuel Haddox, Mohanad Gabani, Wei Zhang, Souad Belmadani, Kaikobad Irani, Mohamed Trebak, Khalid Matrougui

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1900-1909
Number of pages10
JournalArteriosclerosis, thrombosis, and vascular biology
Volume36
Issue number9
DOIs
StatePublished - Sep 1 2016

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

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    Kassan, M., Ait-Aissa, K., Radwan, E., Mali, V., Haddox, S., Gabani, M., Zhang, W., Belmadani, S., Irani, K., Trebak, M., & Matrougui, K. (2016). Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction. Arteriosclerosis, thrombosis, and vascular biology, 36(9), 1900-1909. https://doi.org/10.1161/ATVBAHA.116.307869