L-type Ca Channel Blockers Promote Vascular Remodeling Through Activation of STIM Proteins

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2020 Jul 10

PMID 32641503

Citations 28

Authors

Martin T Johnson

Aparna Gudlur

Xuexin Zhang

Ping Xin

Scott M Emrich

Ryan E Yoast

Raphael Courjaret

Robert M Nwokonko

Wei Li

Nadine Hempel

Khaled Machaca

Donald L Gill

Patrick G Hogan

Mohamed Trebak

Affiliations

Soon will be listed here.

Abstract

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.

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References

Kassan M, Ait-Aissa K, Radwan E, Mali V, Haddox S, Gabani M . Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction. Arterioscler Thromb Vasc Biol. 2016; 36(9):1900-9. PMC: 5061131. DOI: 10.1161/ATVBAHA.116.307869. View

Moussa B, El-Zaher A, Mahrouse M, Ahmed M . Simultaneous determination of amlodipine besylate and atorvastatin calcium in binary mixture by spectrofluorimetry and HPLC coupled with fluorescence detection. Anal Chem Insights. 2013; 8:107-15. PMC: 3825650. DOI: 10.4137/ACI.S12921. View

Bisaillon J, Motiani R, Gonzalez-Cobos J, Potier M, Halligan K, Alzawahra W . Essential role for STIM1/Orai1-mediated calcium influx in PDGF-induced smooth muscle migration. Am J Physiol Cell Physiol. 2010; 298(5):C993-1005. PMC: 2867390. DOI: 10.1152/ajpcell.00325.2009. View

Luik R, Wu M, Buchanan J, Lewis R . The elementary unit of store-operated Ca2+ entry: local activation of CRAC channels by STIM1 at ER-plasma membrane junctions. J Cell Biol. 2006; 174(6):815-25. PMC: 2064336. DOI: 10.1083/jcb.200604015. View

Quignard J, Harricane M, Menard C, Lory P, Nargeot J, Capron L . Transient down-regulation of L-type Ca(2+) channel and dystrophin expression after balloon injury in rat aortic cells. Cardiovasc Res. 2000; 49(1):177-88. DOI: 10.1016/s0008-6363(00)00210-8. View

Franckowiak G, Bechem M, Schramm M, Thomas G . The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels. Eur J Pharmacol. 1985; 114(2):223-6. DOI: 10.1016/0014-2999(85)90631-4. View

Liou J, Kim M, Heo W, Jones J, Myers J, Ferrell Jr J . STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Curr Biol. 2005; 15(13):1235-41. PMC: 3186072. DOI: 10.1016/j.cub.2005.05.055. View

Drazner M . The progression of hypertensive heart disease. Circulation. 2011; 123(3):327-34. DOI: 10.1161/CIRCULATIONAHA.108.845792. View

House S, Potier M, Bisaillon J, Singer H, Trebak M . The non-excitable smooth muscle: calcium signaling and phenotypic switching during vascular disease. Pflugers Arch. 2008; 456(5):769-85. PMC: 2531252. DOI: 10.1007/s00424-008-0491-8. View

10.

Wright J, Musini V, Gill R . First-line drugs for hypertension. Cochrane Database Syst Rev. 2018; 4:CD001841. PMC: 6513559. DOI: 10.1002/14651858.CD001841.pub3. View

11.

Emrich S, Yoast R, Xin P, Zhang X, Pathak T, Nwokonko R . Cross-talk between N-terminal and C-terminal domains in stromal interaction molecule 2 (STIM2) determines enhanced STIM2 sensitivity. J Biol Chem. 2019; 294(16):6318-6332. PMC: 6484143. DOI: 10.1074/jbc.RA118.006801. View

12.

Qi Y, Jiang J, Jiang X, Wang X, Ji S, Han Y . PDGF-BB and TGF-{beta}1 on cross-talk between endothelial and smooth muscle cells in vascular remodeling induced by low shear stress. Proc Natl Acad Sci U S A. 2011; 108(5):1908-13. PMC: 3033274. DOI: 10.1073/pnas.1019219108. View

13.

Zamponi G, Striessnig J, Koschak A, Dolphin A . The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential. Pharmacol Rev. 2015; 67(4):821-70. PMC: 4630564. DOI: 10.1124/pr.114.009654. View

14.

Brown I, Diederich L, Good M, DeLalio L, Murphy S, Cortese-Krott M . Vascular Smooth Muscle Remodeling in Conductive and Resistance Arteries in Hypertension. Arterioscler Thromb Vasc Biol. 2018; 38(9):1969-1985. PMC: 6205219. DOI: 10.1161/ATVBAHA.118.311229. View

15.

Johnson M, Trebak M . ORAI channels in cellular remodeling of cardiorespiratory disease. Cell Calcium. 2019; 79:1-10. PMC: 6461505. DOI: 10.1016/j.ceca.2019.01.005. View

16.

Streb H, Irvine R, Berridge M, Schulz I . Release of Ca2+ from a nonmitochondrial intracellular store in pancreatic acinar cells by inositol-1,4,5-trisphosphate. Nature. 1983; 306(5938):67-9. DOI: 10.1038/306067a0. View

17.

Zhang W, Halligan K, Zhang X, Bisaillon J, Gonzalez-Cobos J, Motiani R . Orai1-mediated I (CRAC) is essential for neointima formation after vascular injury. Circ Res. 2011; 109(5):534-42. PMC: 3164514. DOI: 10.1161/CIRCRESAHA.111.246777. View

18.

Asai M, Takeuchi K, Uchida S, Urushida T, Katoh H, Satoh H . Misinterpretation of the effect of amlodipine on cytosolic calcium concentration with fura-2 fluorospectrometry. Naunyn Schmiedebergs Arch Pharmacol. 2008; 377(4-6):423-7. DOI: 10.1007/s00210-007-0243-x. View

19.

Polster A, Perni S, Bichraoui H, Beam K . Stac adaptor proteins regulate trafficking and function of muscle and neuronal L-type Ca2+ channels. Proc Natl Acad Sci U S A. 2014; 112(2):602-6. PMC: 4299259. DOI: 10.1073/pnas.1423113112. View

20.

Tang L, Gamal El-Din T, Swanson T, Pryde D, Scheuer T, Zheng N . Structural basis for inhibition of a voltage-gated Ca channel by Ca antagonist drugs. Nature. 2016; 537(7618):117-121. PMC: 5161592. DOI: 10.1038/nature19102. View