{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:21:18Z","timestamp":1790691678011,"version":"4.1.0"},"reference-count":77,"publisher":"National Academy of Sciences","issue":"29","license":[{"start":{"date-parts":[[2021,1,8]],"date-time":"2021-01-08T00:00:00Z","timestamp":1610064000000},"content-version":"vor","delay-in-days":184,"URL":"https:\/\/www.pnas.org\/site\/aboutpnas\/licenses.xhtml"}],"funder":[{"DOI":"10.13039\/100000050","name":"HHS | NIH | National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R35 HL150778"],"award-info":[{"award-number":["R35 HL150778"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01 AI084167"],"award-info":[{"award-number":["R01 AI084167"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2020,7,21]]},"abstract":"<jats:p>\n                    Voltage-gated L-type Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channel (Ca\n                    <jats:sub>v<\/jats:sub>\n                    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\n                    <jats:sup>2+<\/jats:sup>\n                    signaling machinery, including down-regulation of Ca\n                    <jats:sub>v<\/jats:sub>\n                    1.2 channels and up-regulation of the endoplasmic reticulum (ER) stromal-interacting molecule (STIM) Ca\n                    <jats:sup>2+<\/jats:sup>\n                    sensor proteins and the plasma membrane ORAI Ca\n                    <jats:sup>2+<\/jats:sup>\n                    channels. STIM\/ORAI proteins mediate store-operated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry (SOCE) and drive fibro-proliferative gene programs during cardiovascular remodeling. SOCE is activated by agonists that induce depletion of ER Ca\n                    <jats:sup>2+<\/jats:sup>\n                    , causing STIM to activate ORAI. Here, we show that the three major classes of LCCBs activate STIM\/ORAI-mediated Ca\n                    <jats:sup>2+<\/jats:sup>\n                    entry in VSMCs. LCCBs act on the STIM N terminus to cause STIM relocalization to junctions and subsequent ORAI activation in a Ca\n                    <jats:sub>v<\/jats:sub>\n                    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\n                    <jats:sup>2+<\/jats:sup>\n                    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.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2007598117","type":"journal-article","created":{"date-parts":[[2020,7,8]],"date-time":"2020-07-08T20:06:56Z","timestamp":1594238816000},"page":"17369-17380","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":57,"title":["L-type Ca\n                    <sup>2+<\/sup>\n                    channel blockers promote vascular remodeling through activation of STIM proteins"],"prefix":"10.1073","volume":"117","author":[{"given":"Martin T.","family":"Johnson","sequence":"first","affiliation":[{"name":"Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 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