Johnson Martin T, Gudlur Aparna, Zhang Xuexin, Xin Ping, Emrich Scott M, Yoast Ryan E, Courjaret Raphael, Nwokonko Robert M, Li Wei, Hempel Nadine, Machaca Khaled, Gill Donald L, Hogan Patrick G, Trebak Mohamed
Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.
Division of Signaling and Gene Expression, La Jolla Institute for Immunology, La Jolla, CA 92037.
Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17369-17380. doi: 10.1073/pnas.2007598117. Epub 2020 Jul 8.
Voltage-gated L-type Ca channel (Ca1.2) blockers (LCCBs) are major drugs for treating hypertension, the preeminent risk factor for heart failure. Vascular smooth muscle cell (VSMC) remodeling is a pathological hallmark of chronic hypertension. VSMC remodeling is characterized by molecular rewiring of the cellular Ca signaling machinery, including down-regulation of Ca1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromal-interacting molecule (STIM) Ca sensor proteins and the plasma membrane ORAI Ca channels. STIM/ORAI proteins mediate store-operated Ca entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca, causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM/ORAI-mediated Ca entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Ca1.2-independent and store depletion-independent manner. LCCB-induced promotion of VSMC remodeling requires STIM1, which is up-regulated in VSMCs from hypertensive rats. Epidemiology showed that LCCBs are more associated with heart failure than other antihypertensive drugs in patients. Our findings unravel a mechanism of LCCBs action on Ca signaling and demonstrate that LCCBs promote vascular remodeling through STIM-mediated activation of ORAI. Our data indicate caution against the use of LCCBs in elderly patients or patients with advanced hypertension and/or onset of cardiovascular remodeling, where levels of STIM and ORAI are elevated.
电压门控L型钙通道（Ca1.2）阻滞剂（LCCBs）是治疗高血压的主要药物，而高血压是心力衰竭的首要危险因素。血管平滑肌细胞（VSMC）重塑是慢性高血压的病理标志。VSMC重塑的特征是细胞钙信号传导机制的分子重排，包括Ca1.2通道的下调以及内质网（ER）基质相互作用分子（STIM）钙传感蛋白和质膜ORAI钙通道的上调。STIM/ORAI蛋白介导储存操纵性钙内流（SOCE），并在心血管重塑过程中驱动纤维增生性基因程序。SOCE由诱导ER钙耗竭的激动剂激活，导致STIM激活ORAI。在此，我们表明三大类LCCBs可激活VSMCs中STIM/ORAI介导的钙内流。LCCBs作用于STIM的N端，导致STIM重新定位到连接处，并随后以不依赖Ca1.2和不依赖储存耗竭的方式激活ORAI。LCCB诱导的VSMC重塑促进需要STIM1，而STIM1在高血压大鼠的VSMCs中上调。流行病学显示，在患者中，LCCBs比其他抗高血压药物与心力衰竭的相关性更强。我们的研究结果揭示了LCCBs对钙信号传导的作用机制，并证明LCCBs通过STIM介导的ORAI激活促进血管重塑。我们的数据表明，对于老年患者或患有晚期高血压和/或心血管重塑的患者，应谨慎使用LCCBs，因为这些患者中STIM和ORAI的水平会升高。
