{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T18:49:27Z","timestamp":1789843767220,"version":"4.0.1"},"reference-count":43,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,2,24]],"date-time":"2023-02-24T00:00:00Z","timestamp":1677196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["OD025230"],"award-info":[{"award-number":["OD025230"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the UTA College of Nursing and Health Innovation","award":["OD025230"],"award-info":[{"award-number":["OD025230"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Epirubicin (EPI) is one of the most widely used anthracycline chemotherapy drugs, yet its cardiotoxicity severely limits its clinical application. Altered intracellular Ca2+ homeostasis has been shown to contribute to EPI-induced cell death and hypertrophy in the heart. While store-operated Ca2+ entry (SOCE) has recently been linked with cardiac hypertrophy and heart failure, its role in EPI-induced cardiotoxicity remains unknown. Using a publicly available RNA-seq dataset of human iPSC-derived cardiomyocytes, gene analysis showed that cells treated with 2 \u00b5M EPI for 48 h had significantly reduced expression of SOCE machinery genes, e.g., Orai1, Orai3, TRPC3, TRPC4, Stim1, and Stim2. Using HL-1, a cardiomyocyte cell line derived from adult mouse atria, and Fura-2, a ratiometric Ca2+ fluorescent dye, this study confirmed that SOCE was indeed significantly reduced in HL-1 cells treated with EPI for 6 h or longer. However, HL-1 cells presented increased SOCE as well as increased reactive oxygen species (ROS) production at 30 min after EPI treatment. EPI-induced apoptosis was evidenced by disruption of F-actin and increased cleavage of caspase-3 protein. The HL-1 cells that survived to 24 h after EPI treatment demonstrated enlarged cell sizes, up-regulated expression of brain natriuretic peptide (a hypertrophy marker), and increased NFAT4 nuclear translocation. Treatment by BTP2, a known SOCE blocker, decreased the initial EPI-enhanced SOCE, rescued HL-1 cells from EPI-induced apoptosis, and reduced NFAT4 nuclear translocation and hypertrophy. This study suggests that EPI may affect SOCE in two phases: the initial enhancement phase and the following cell compensatory reduction phase. Administration of a SOCE blocker at the initial enhancement phase may protect cardiomyocytes from EPI-induced toxicity and hypertrophy.<\/jats:p>","DOI":"10.3390\/cells12050723","type":"journal-article","created":{"date-parts":[[2023,2,27]],"date-time":"2023-02-27T04:05:40Z","timestamp":1677470740000},"page":"723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Blocking Store-Operated Ca2+ Entry to Protect HL-1 Cardiomyocytes from Epirubicin-Induced Cardiotoxicity"],"prefix":"10.3390","volume":"12","author":[{"given":"Xian","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"},{"name":"Department of Graduate Nursing, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Graduate Nursing, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"},{"name":"Bone and Muscle Research Center, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6316-7068","authenticated-orcid":false,"given":"Sangyong","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Graduate Nursing, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chuanxi","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Surgery, Division of Surgical Sciences, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2495-4568","authenticated-orcid":false,"given":"Xiaoli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4105-901X","authenticated-orcid":false,"given":"Zui","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"},{"name":"Department of Graduate Nursing, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"},{"name":"Bone and Muscle Research Center, College of Nursing and Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,24]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021, September 30). 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