Modar Kassan1, Karima Ait-Aissa1, Eman Radwan1, Vishal Mali1, Samuel Haddox1, Mohanad Gabani1, Wei Zhang1, Souad Belmadani1, Kaikobad Irani1, Mohamed Trebak2, Khalid Matrougui2. 1. From the Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, LA (M.K., K.M.); Department of Physiological Sciences, EVMS, Norfolk, VA (M.K., K.A.-A., E.R., V.M., S.H., S.B., K.M.); Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA (W.Z., M.T); and Department of Internal Medicine, University of Iowa, Iowa City (K.M., M.G., K.I.). 2. From the Department of Physiology, Hypertension and Renal Center of Excellence, Tulane University, New Orleans, LA (M.K., K.M.); Department of Physiological Sciences, EVMS, Norfolk, VA (M.K., K.A.-A., E.R., V.M., S.H., S.B., K.M.); Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA (W.Z., M.T); and Department of Internal Medicine, University of Iowa, Iowa City (K.M., M.G., K.I.). matrouk@evms.edu mtrebak@hmc.psu.edu.
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 (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-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 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.
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-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 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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