Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction

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 up-regulation during Angiotensin II-induced hypertension was associated with enhanced endoplasmic reticulum (ER) stress and smooth muscle STIM1 was required for ER stress-induced vascular dysfunction through TGF-β and NADPH oxidase-dependent pathways. Accordingly, knockout mice for the ER stress pro-apoptotic transcriptional factor, CHOP (CHOP−/−) were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with Angiotensin II, but not Stim1SMC−/− or CHOP−/− mice showed elevated vascular NADPH oxidase activity and reduced phosphorylated endothelial Nitric Oxide Synthase (eNOS), cGMP and nitrite levels. Conclusion 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 Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…STIM1 is an ER Ca 2ϩ sensor, which plays a critical role in the activation of Orai1 channels at the plasma membrane that mediate store-operated Ca 2ϩ entry. Smooth muscle-specific STIM1-deficient mice do not develop hypertension upon ANG II infusion; the vasculature of STIM1-deficient mice exhibits impaired ER stress responses and is protected from ANG II-induced endothelial dysfunction (464).…”

“…Moreover, ER stress and UPR have been shown to play causative roles in various ANG II-induced pathologies, including brain (1216) and vascular (465,587) regulation of hypertension, endothelial dysfunction (465), cardiac hypertrophy and fibrosis (465), and vascular hypertrophy and fibrosis (465,989,1035). Specifically, CHOPϪ/Ϫ mice are protected from ANG IIinduced NADPH oxidase activation, hypertension, and cardiovascular pathology (464). ANG II-induced ER stress exists downstream of the ADAM17/EGFR transactivation cascade (1034,1035) and stromal interaction molecule 1 (STIM1) induction (464), and upstream of cardiac (465) and renal TGF-␤ induction (1118), vascular apoptotic pathway (989), and brain SFO NF-B activation (1218).…”

“…Specifically, CHOPϪ/Ϫ mice are protected from ANG IIinduced NADPH oxidase activation, hypertension, and cardiovascular pathology (464). ANG II-induced ER stress exists downstream of the ADAM17/EGFR transactivation cascade (1034,1035) and stromal interaction molecule 1 (STIM1) induction (464), and upstream of cardiac (465) and renal TGF-␤ induction (1118), vascular apoptotic pathway (989), and brain SFO NF-B activation (1218). While these studies suggest that ER stress is vital for ANG II-induced signal transduction and pathologies, it remains elusive whether AT 1 R stimulation increases unfolded proteins in ER, or if so, how it happens.…”

Store-operated calcium channels: Potential target for the therapy of hypertension

“…Since STIM1 is a key regulator of Ca 2+ homeostasis for supporting communications between the ER/SR and the plasma membrane, its upregulation could lead to direct or indirect ER/SR stress, as well as dictating the development of cardiovascular complications in hypertensive conditions. Wild-type mice infused with angiotensin II have been shown to develop hypertension, cardiac hypertrophy, perivascular fibrosis and endothelial dysfunction associated with enhanced STIM1 expression in heart and blood vessels, in study by Kassan et al (2016). The same authors reported that STIM1 up-regulation during angiotensin IIinduced hypertension was associated with enhanced ER/SR stress through TGF-β and NADPH oxidase-dependent pathways.…”

“…Conversely, their dysregulation promotes several pathophysiologies, including atherosclerosis, arterial stenosis, thrombosis, and hypertension (Ruhle and Trebak, 2013;Tanwar et al, 2017). There is a strong correlation between hypertension and enhanced STIM and/or Orai protein expression (Kassan et al, 2016;Pulina et al, 2013;Spinelli and Trebak, 2016;Zhang and Trebak, 2011). It has been proposed that augmented Ca 2+ influx through SOCE pathways, STIM1/Orai 1, may contribute in potentiating vascular reactivity (Giachini et al, , 2012 and vascular tone and force generation (Goulopoulou and Webb, 2014;Kitazono et al, 2002;Tanwar et al, 2017) (Fig.…”