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

doi:10.1161/ATVBAHA.116.307869

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Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction

Journal article

Open access

Peer reviewed

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, …

Arteriosclerosis, thrombosis, and vascular biology, Vol.36(9), pp.1900-1909

09/2016

DOI: 10.1161/ATVBAHA.116.307869

PMCID: PMC5061131

PMID: 27470514

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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.

Angiotensin II

Animals

Blood Pressure - drug effects

Cardiomegaly - genetics

Cardiomegaly - metabolism

Cardiomegaly - physiopathology

Cardiomegaly - prevention & control

Cyclic GMP - metabolism

Disease Models, Animal

Dose-Response Relationship, Drug

Endoplasmic Reticulum Stress

Fibrosis

Genetic Predisposition to Disease

Hypertension - genetics

Hypertension - metabolism

Hypertension - physiopathology

Hypertension - prevention & control

Male

Mice, Knockout

Muscle, Smooth, Vascular - drug effects

Muscle, Smooth, Vascular - metabolism

Muscle, Smooth, Vascular - pathology

Muscle, Smooth, Vascular - physiopathology

Myocardium - metabolism

Myocardium - pathology

NADPH Oxidases - metabolism

Nitric Oxide Synthase Type III - metabolism

Nitrites - metabolism

Phenotype

Phosphorylation

Reactive Oxygen Species - metabolism

Signal Transduction

Stromal Interaction Molecule 1 - deficiency

Stromal Interaction Molecule 1 - genetics

Stromal Interaction Molecule 1 - metabolism

Time Factors

Transcription Factor CHOP - deficiency

Transcription Factor CHOP - genetics

Transforming Growth Factor beta - metabolism

Vasodilation - drug effects

Vasodilator Agents - pharmacology

Details

Title: Subtitle: Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction
Creators: Modar Kassan - University of Iowa
Karima Ait-Aissa - Eastern Virginia Medical School
Eman Radwan - Eastern Virginia Medical School
Vishal Mali - Eastern Virginia Medical School
Samuel Haddox - Eastern Virginia Medical School
Mohanad Gabani - University of Iowa
Wei Zhang - Pennsylvania State University
Souad Belmadani - Eastern Virginia Medical School
Kaikobad Irani - University of Iowa
Mohamed Trebak - Penn State Cancer Institute
Khalid Matrougui - Eastern Virginia Medical School
Resource Type: Journal article
Publication Details: Arteriosclerosis, thrombosis, and vascular biology, Vol.36(9), pp.1900-1909
DOI: 10.1161/ATVBAHA.116.307869
PMID: 27470514
PMCID: PMC5061131
NLM abbreviation: Arterioscler Thromb Vasc Biol
ISSN: 1079-5642
eISSN: 1524-4636
Grant note: R01 HL097111 / NHLBI NIH HHS T32 HL007121 / NHLBI NIH HHS R21 AG050072 / NIA NIH HHS R01 HL095566 / NHLBI NIH HHS R01 HL123364 / NHLBI NIH HHS
Language: English
Date published: 09/2016
Academic Unit: Cardiovascular Medicine; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine
Record Identifier: 9984312986802771

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