Orai1 Participates in Coronary Artery Dysfunction Caused by Hypertension via Regulating Smooth Muscle Cell Phenotype Transformation

ABSTRACT Hypertension plays a critical role in the development of vascular remodeling and atherosclerosis. STIM/Orai1 proteins mediate store‐operated Ca 2+ entry (SOCE), which is one of the cellular Ca 2+ signaling machinery involved in the pathological process of cardiovascular remodeling. However, the role and mechanism of Orai1/Orai1 mediated SOCE in coronary artery dysfunction caused by hypertension remain incompletely elucidated. The present study aimed to investigate the role of the Orai1/NFAT/calcineurin signaling pathway in hypertension‐induced coronary vasoconstriction impairment utilizing spontaneous hypertension rats (SHRs) and coronary arterial smooth muscle cells (CASMCs) exposed to high hydrostatic pressure (180 mmHg). Here, we found that agonists (5‐HT, U46619, and ET‐1) induced coronary artery constriction that was significantly reduced in SHRs compared with Wistar rats. The SOCE inhibitors SKF96365 and 2‐APB also significantly inhibited coronary artery constriction in both SHRs and Wistar rats; only the inhibitory effect of low concentrations (50 μM) of 2‐APB on SHRs was weaker than that of Wistar rats. Hypertension/high hydrostatic pressure (180 mmHg) induced phenotypic transformation of CASMCs, with an increase in the expression of STIM1/Orai1, Calcineurin‐NFAT2, and the synthetic phenotypic marker protein OPN, and a decrease in the contractile phenotypic marker protein SMMHC. The intervention of Orai1/Orai1 mediated SOCE (overexpression with ad‐Orai1, inhibition of SOCE channel with BTP2 or downregulation with Orai1 siRNA) regulated STIM1, Calcineurin‐NFAT2 expression, and contraction/synthesis phenotypic markers. Together, these findings suggest that hypertension leads to coronary vascular dysfunction via the upregulation of Orai1, which is required for the phenotypic transformation of VSMCs by activating the Calcineurin‐NFAT signaling pathway.