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

16 Citations (Scopus)

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

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Smooth Muscle
Endoplasmic Reticulum Stress
Hypertension
Angiotensin II
Pathology
NADP
Blood Vessels
Oxidoreductases
CCAAT-Enhancer-Binding Proteins
Nitric Oxide Synthase Type III
Cardiomegaly
Transforming Growth Factors
Nitrites
Knockout Mice
Fibrosis
Cardiovascular Diseases
Up-Regulation
Heart Failure
Stroke
Stromal Interaction Molecule 1

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine

Cite this

Kassan, M., Ait-Aissa, K., Radwan, E., Mali, V., Haddox, S., Gabani, 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
Kassan, Modar ; Ait-Aissa, Karima ; Radwan, Eman ; Mali, Vishal ; Haddox, Samuel ; Gabani, Mohanad ; Zhang, Wei ; Belmadani, Souad ; Irani, Kaikobad ; Trebak, Mohamed ; Matrougui, Khalid. / Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction. In: Arteriosclerosis, thrombosis, and vascular biology. 2016 ; Vol. 36, No. 9. pp. 1900-1909.
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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, vol. 36, no. 9, pp. 1900-1909. https://doi.org/10.1161/ATVBAHA.116.307869

Essential role of smooth muscle STIM1 in hypertension and cardiovascular dysfunction. / Kassan, Modar; Ait-Aissa, Karima; Radwan, Eman; Mali, Vishal; Haddox, Samuel; Gabani, Mohanad; Zhang, Wei; Belmadani, Souad; Irani, Kaikobad; Trebak, Mohamed; Matrougui, Khalid.

In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 36, No. 9, 01.09.2016, p. 1900-1909.

Research output: Contribution to journalArticle

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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

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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