{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T20:13:21Z","timestamp":1787688801265,"version":"build-2784847793"},"reference-count":26,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["U23A20171"],"award-info":[{"award-number":["U23A20171"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32071115"],"award-info":[{"award-number":["32071115"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32271154"],"award-info":[{"award-number":["32271154"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32571296"],"award-info":[{"award-number":["32571296"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["32471164"],"award-info":[{"award-number":["32471164"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Acta Physiologica"],"published-print":{"date-parts":[[2026,5]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Phospholamban (PLN) is a key regulator of sarco\u2010endoplasmic reticulum calcium ATPase (SERCA) activity and myocardial contractility, but its expression control remains incompletely understood. This study seeks to clarify the molecular mechanism of PLN regulation and its functional relevance in cardiac physiology.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p>Using cardiomyocyte\u2010specific ZBTB20 knockout (CZB20KO) mice and primary cardiomyocytes, we demonstrated that ZBTB20 deficiency significantly reduced PLN protein at a higher magnitude than its mRNA levels, accompanied by a marked increase in the expression levels of miR\u2010221 and miR\u2010222 derived from the same gene cluster. Cardiomyocyte\u2010specific deletion of miR\u2010221\/222 alone did not affect cardiac PLN expression in the mice, but fully restored the expression of PLN protein and the basal cardiac contractility in the context of ZBTB20 deficiency, as evidenced by normal left ventricular ejection fraction and fractional shortening compared to control mice. Through luciferase reporter assays with 3\u2032UTR binding site mutagenesis and gain\/loss\u2010of\u2010function experiments, we identified miR\u2010221 but not its paralog miR\u2010222 as a direct regulator of PLN by targeting its 3\u2032UTR of mRNA. Moreover, cardiomyocyte\u2010specific overexpression of miR\u2010221 in mice led to a reduction in cardiac PLN protein levels. ChIP assay did not reveal significant binding of ZBTB20 to the miR\u2010221\/222 gene cluster.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study identifies miR\u2010221 as a novel regulator of cardiac PLN expression and a mediator of the regulation of PLN by ZBTB20. Thus this work provides insights into the regulation of basal contractility and functional reserve of the heart.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70217","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T10:40:53Z","timestamp":1775731253000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["<scp>miR<\/scp>\n                    \u2010221 Mediates the Regulation of Phospholamban Expression and Cardiac Contractility by\n                    <scp>ZBTB20<\/scp>"],"prefix":"10.1111","volume":"242","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2280-8337","authenticated-orcid":false,"given":"Qiu\u2010Xiao","family":"Ren","sequence":"first","affiliation":[{"name":"Department of Pathophysiology, National Key Laboratory of Immunity &amp; Inflammation Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7408-7637","authenticated-orcid":false,"given":"Ya\u2010Jin","family":"Liu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases Tianjin Institute of Endocrinology &amp; Chu Hsien\u2010I Memorial Hospital, Tianjin Medical University Tianjin  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7965-1727","authenticated-orcid":false,"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pathophysiology, National Key Laboratory of Immunity &amp; Inflammation Naval Medical University  Shanghai China"},{"name":"Experimental Teaching Center, College of Basic Medical Sciences Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1012-4536","authenticated-orcid":false,"given":"Xiaowei","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Diseases, Changhai Hospital Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-5606-7369","authenticated-orcid":false,"given":"Qian","family":"Zhao","sequence":"additional","affiliation":[{"name":"Experimental Teaching Center, College of Basic Medical Sciences Naval Medical University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3848-7040","authenticated-orcid":false,"given":"Ya\u2010Nan","family":"Cao","sequence":"additional","affiliation":[{"name":"National Clinical Research Center for Metabolic Diseases, Department of Endocrine and Metabolic Diseases, Shanghai Institute for Endocrine and Metabolic Diseases, Ruijin Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7393-2544","authenticated-orcid":false,"given":"Ru\u2010Tai","family":"Hui","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences and Peking Union Medical College  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6297-9037","authenticated-orcid":false,"given":"Huang\u2010Tian","family":"Yang","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Tissue Microenvironment and Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health Chinese Academy of Sciences  China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7725-9166","authenticated-orcid":false,"given":"Yi","family":"Zhu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases Tianjin Institute of Endocrinology &amp; 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