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L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins.
Proc Natl Acad Sci U S A. 2020 07 21; 117(29):17369-17380.PN

Abstract

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) stromal-interacting molecule (STIM) Ca2+ sensor proteins and the plasma membrane ORAI Ca2+ channels. STIM/ORAI proteins mediate store-operated 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 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 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.

Authors+Show Affiliations

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.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033. Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033. Department of Pediatrics, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033. Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033.Department of Physiology and Biophysics, Weill Cornell Medicine Qatar, Education City, Qatar Foundation, Doha, Qatar.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.Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033; mtrebak@psu.edu. Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, PA 17033.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

32641503

Citation

Johnson, Martin T., et al. "L-type Ca2+ Channel Blockers Promote Vascular Remodeling Through Activation of STIM Proteins." Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 29, 2020, pp. 17369-17380.
Johnson MT, Gudlur A, Zhang X, et al. L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins. Proc Natl Acad Sci U S A. 2020;117(29):17369-17380.
Johnson, M. T., Gudlur, A., Zhang, X., Xin, P., Emrich, S. M., Yoast, R. E., Courjaret, R., Nwokonko, R. M., Li, W., Hempel, N., Machaca, K., Gill, D. L., Hogan, P. G., & Trebak, M. (2020). L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins. Proceedings of the National Academy of Sciences of the United States of America, 117(29), 17369-17380. https://doi.org/10.1073/pnas.2007598117
Johnson MT, et al. L-type Ca2+ Channel Blockers Promote Vascular Remodeling Through Activation of STIM Proteins. Proc Natl Acad Sci U S A. 2020 07 21;117(29):17369-17380. PubMed PMID: 32641503.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins. AU - Johnson,Martin T, AU - Gudlur,Aparna, AU - Zhang,Xuexin, AU - Xin,Ping, AU - Emrich,Scott M, AU - Yoast,Ryan E, AU - Courjaret,Raphael, AU - Nwokonko,Robert M, AU - Li,Wei, AU - Hempel,Nadine, AU - Machaca,Khaled, AU - Gill,Donald L, AU - Hogan,Patrick G, AU - Trebak,Mohamed, Y1 - 2020/07/08/ PY - 2020/7/10/pubmed PY - 2020/9/15/medline PY - 2020/7/10/entrez KW - Cav1.2 KW - STIM1 KW - calcium signaling KW - hypertension KW - vascular remodeling SP - 17369 EP - 17380 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 117 IS - 29 N2 - 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) stromal-interacting molecule (STIM) Ca2+ sensor proteins and the plasma membrane ORAI Ca2+ channels. STIM/ORAI proteins mediate store-operated 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 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 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. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/32641503/L_type_Ca2+_channel_blockers_promote_vascular_remodeling_through_activation_of_STIM_proteins_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=32641503 DB - PRIME DP - Unbound Medicine ER -