title: Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction.
abstract: Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.).
authors.forename: Modar
authors.initials: M
authors.lastname: Kassan
authors.affiliation: 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.).
authors.forename: Karima
authors.initials: K
authors.lastname: Ait-Aissa
authors.affiliation: 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.).
authors.forename: Eman
authors.initials: E
authors.lastname: Radwan
authors.affiliation: 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.).
authors.forename: Vishal
authors.initials: V
authors.lastname: Mali
authors.affiliation: 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.).
authors.forename: Samuel
authors.initials: S
authors.lastname: Haddox
authors.affiliation: 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.).
authors.forename: Mohanad
authors.initials: M
authors.lastname: Gabani
authors.affiliation: 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.).
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: 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.).
authors.forename: Souad
authors.initials: S
authors.lastname: Belmadani
authors.affiliation: 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.).
authors.forename: Kaikobad
authors.initials: K
authors.lastname: Irani
authors.affiliation: 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.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Trebak
authors.affiliation: 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.
authors.forename: Khalid
authors.initials: K
authors.lastname: Matrougui
mesh_terms: D000804:Angiotensin II; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D006152:Cyclic GMP / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress; D005355:Fibrosis; D020022:Genetic Predisposition to Disease; D006973:Hypertension / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009573:Nitrites / Q000378:metabolism; D010641:Phenotype; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D000071737:Stromal Interaction Molecule 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000172:deficiency / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: C497250:Ddit3 protein, mouse; D009573:Nitrites; D017382:Reactive Oxygen Species; C100757:Stim1 protein, mouse; D000071737:Stromal Interaction Molecule 1; D016212:Transforming Growth Factor beta; D014665:Vasodilator Agents; D000804:Angiotensin II; D051742:Transcription Factor CHOP; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D019255:NADPH Oxidases; D006152:Cyclic GMP
keywords: ER stress; cardiac hypertrophy; endothelial nitric oxide synthase; hypertension; nicotinamide adenine dinucleotide phosphate; stromal interaction molecule 1; vascular reactivity