L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins
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 rewirin...
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Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 117; no. 29; pp. 17369 - 17380 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Washington
National Academy of Sciences
21.07.2020
|
Series | From the Cover |
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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) 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. |
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AbstractList | 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. 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. L-type Ca 2+ channel (Ca v 1.2) blockers (LCCBs) represent a large family of drugs widely used in the clinic for over 70 y to treat hypertension, angina, and cardiac arrhythmias. Using genetically modified cells, animal models, and human studies, we demonstrate that all the three major classes of LCCBs activate STIM proteins by acting on a 10-amino acid N-terminal region located in the endoplasmic reticulum lumen. The activation of STIM triggers store-operated Ca 2+ entry and promotes vascular remodeling. These results provide unique mechanistic insights into how widely used drugs activate a Ca 2+ signaling pathway and suggest that the use of LCCBs in patients with chronic hypertension, where levels of STIM proteins and vascular remodeling are already enhanced, should be avoided. Voltage-gated L-type Ca 2+ channel (Ca v 1.2) 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 2+ signaling machinery, including down-regulation of Ca v 1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromal-interacting molecule (STIM) Ca 2+ sensor proteins and the plasma membrane ORAI Ca 2+ channels. STIM/ORAI proteins mediate store-operated Ca 2+ entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca 2+ , causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM/ORAI-mediated Ca 2+ entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Ca v 1.2-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 2+ 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. |
Author | Hogan, Patrick G. Li, Wei Emrich, Scott M. Xin, Ping Zhang, Xuexin Nwokonko, Robert M. Gudlur, Aparna Machaca, Khaled Courjaret, Raphael Yoast, Ryan E. Gill, Donald L. Johnson, Martin T. Hempel, Nadine |
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Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Mark T. Nelson, University of Vermont, Burlington, VT, and approved June 2, 2020 (received for review April 26, 2020) Author contributions: M.T.J., K.M., P.G.H., and M.T. designed research; M.T.J., A.G., X.Z., P.X., S.M.E., R.E.Y., R.C., and R.M.N. performed research; W.L., N.H., and D.L.G. contributed new reagents/analytic tools; M.T.J., A.G., X.Z., R.C., K.M., P.G.H., and M.T. analyzed data; and M.T.J. and M.T. wrote the paper. |
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Snippet | Voltage-gated L-type Ca2+ channel (Cav1.2) blockers (LCCBs) are major drugs for treating hypertension, the preeminent risk factor for heart failure. Vascular... L-type Ca 2+ channel (Ca v 1.2) blockers (LCCBs) represent a large family of drugs widely used in the clinic for over 70 y to treat hypertension, angina, and... |
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StartPage | 17369 |
SubjectTerms | 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 |
Title | L-type Ca2+ channel blockers promote vascular remodeling through activation of STIM proteins |
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