{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T12:18:10Z","timestamp":1791980290580,"version":"4.4.0"},"reference-count":51,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"8","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2021,4,20]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Orai3 is a mammalian\u2010specific member of the Orai family (Orai1\u20123) and a component of the store\u2010operated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      entry channels. There is little understanding of the role of Orai channels in cardiomyocytes, and its role in cardiac function remains unexplored. Thus, we developed mice lacking Orai1 and Orai3 to address their role in cardiac homeostasis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We generated constitutive and inducible cardiomyocyte\u2010specific Orai3 knockout (Orai3\n                      <jats:sup>cKO<\/jats:sup>\n                      ) mice. Constitutive Orai3\u2010loss led to ventricular dysfunction progressing to dilated cardiomyopathy and heart failure. Orai3\n                      <jats:sup>cKO<\/jats:sup>\n                      mice subjected to pressure overload developed a fulminant dilated cardiomyopathy with rapid heart failure onset, characterized by interstitial fibrosis and apoptosis. Ultrastructural analysis of Orai3\u2010deficient cardiomyocytes showed abnormal M\u2010 and Z\u2010line morphology. The greater density of condensed mitochondria in Orai3\u2010deficient cardiomyocytes was associated with the upregulation of DRP1 (dynamin\u2010related protein 1). Cardiomyocytes isolated from Orai3\n                      <jats:sup>cKO<\/jats:sup>\n                      mice exhibited profoundly altered myocardial Ca\n                      <jats:sup>2+<\/jats:sup>\n                      cycling and changes in the expression of critical proteins involved in the Ca\n                      <jats:sup>2+<\/jats:sup>\n                      clearance mechanisms. Upregulation of TRPC6 (transient receptor potential canonical type 6) channels was associated with upregulation of the RCAN1 (regulator of calcineurin 1), indicating the activation of the calcineurin signaling pathway in Orai3\n                      <jats:sup>cKO<\/jats:sup>\n                      mice. A more dramatic cardiac phenotype emerged when Orai3 was removed in adult mice using a tamoxifen\u2010inducible Orai3\n                      <jats:sup>cKO<\/jats:sup>\n                      mouse. The removal of Orai1 from adult cardiomyocytes did not change the phenotype of tamoxifen\u2010inducible Orai3\n                      <jats:sup>cKO<\/jats:sup>\n                      mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Our results identify a critical role for Orai3 in the heart. We provide evidence that Orai3\u2010mediated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      signaling is required for maintaining sarcomere integrity and proper mitochondrial function in adult mammalian cardiomyocytes.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.120.019486","type":"journal-article","created":{"date-parts":[[2021,4,14]],"date-time":"2021-04-14T05:02:04Z","timestamp":1618376524000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":21,"title":["Cardiac\u2010Specific Deletion of Orai3 Leads to Severe Dilated Cardiomyopathy and Heart Failure in Mice"],"prefix":"10.1161","volume":"10","author":[{"given":"Jesse","family":"Gammons","sequence":"first","affiliation":[{"name":"Department of Physiology University of Tennessee Health Science Center Memphis 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