L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 29; pp. 17369 - 17380
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: Washington National Academy of Sciences 21.07.2020
• Series: From the Cover
• Subjects: Activation; Antihypertensives; Biological Sciences; Calcium channels; Calcium channels (L-type); Calcium channels (voltage-gated); Calcium influx; Calcium ions; Calcium signalling; Channels; Congestive heart failure; Depletion; Drugs; Endoplasmic reticulum; Epidemiology; Heart failure; Hypertension; Muscles; Proteins; Rewiring; Risk analysis; Risk factors; Signaling; Smooth muscle; STIM1 protein
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2007598117

Voltage-gated L-type Ca2+ channel (Cav1.2) 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 Ca2+ signaling machinery, including down-regulation of Cav1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromalinteracting molecule (STIM) Ca2+ sensor proteins and the plasma membrane ORAI Ca2+ channels. STIM/ORAI proteins mediate storeoperated Ca2+ entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca2+, causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM/ORAI-mediated Ca2+ entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Cav1.2-independent and store depletionindependent 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 Ca2+ 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.