{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T02:59:36Z","timestamp":1791946776889,"version":"4.3.4"},"reference-count":38,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB 829"],"award-info":[{"award-number":["SFB 829"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["PO1 AG017242"],"award-info":[{"award-number":["PO1 AG017242"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001826","name":"ZonMw","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aging Cell"],"published-print":{"date-parts":[[2023,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross\u2010complementation group 1 (ERCC1), either systemically or cardiomyocyte\u2010restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6\u00a0months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the <jats:italic>ERCC1<\/jats:italic> and <jats:italic>XPG<\/jats:italic> gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte\u2010restricted DNA repair\u2010deficient mouse mutants as <jats:italic>bona fide<\/jats:italic> models of heart failure.<\/jats:p>","DOI":"10.1111\/acel.13768","type":"journal-article","created":{"date-parts":[[2023,2,9]],"date-time":"2023-02-09T07:55:49Z","timestamp":1675929349000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["<scp>DNA<\/scp> repair in cardiomyocytes is critical for maintaining cardiac function in mice"],"prefix":"10.1111","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3405-654X","authenticated-orcid":false,"given":"Martine","family":"de Boer","sequence":"first","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology Thoraxcenter, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maaike","family":"te Lintel\u00a0Hekkert","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology Thoraxcenter, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bibi S.","family":"van Thiel","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC  Rotterdam The Netherlands"},{"name":"Department of Vascular Surgery, Erasmus MC  Rotterdam The Netherlands"},{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonie","family":"Martens","sequence":"additional","affiliation":[{"name":"Department of Genetic Epidemiology, Institute of Human Genetics University Hospital M\u00fcnster  M\u00fcnster Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime M.","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marion G. J.","family":"de Kleijnen","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology Thoraxcenter, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanto","family":"Ridwan","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC  Rotterdam The Netherlands"},{"name":"Department of Radiotherapy, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanti","family":"Octavia","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology Thoraxcenter, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elza D.","family":"van Deel","sequence":"additional","affiliation":[{"name":"Department of Physiology, Amsterdam Cardiovascular Sciences Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lau A.","family":"Blonden","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology Thoraxcenter, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renata M. C.","family":"Brandt","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sander","family":"Barnhoorn","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paula K.","family":"Bautista\u2010Ni\u00f1o","sequence":"additional","affiliation":[{"name":"Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC  Rotterdam The Netherlands"},{"name":"Centro de Investigaciones Fundaci\u00f3n Cardiovascular de Colombia\u2010 FCV  Bucaramanga Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilona","family":"Krabbendam\u2010Peters","sequence":"additional","affiliation":[{"name":"Division of Experimental Cardiology, Department of Cardiology Thoraxcenter, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rianne","family":"Wolswinkel","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Cardiology, Heart Center Academic Medical Center, University of Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Banafsheh","family":"Arshi","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohsen","family":"Ghanbari","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Kupatt","sequence":"additional","affiliation":[{"name":"I. Medizinische Klinik und Poliklinik University Clinic Rechts der Isar, Technical University of Munich  Munich Germany"},{"name":"DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance  Munich Germany"},{"name":"Walter\u2010Brendel\u2010Centre for Experimental Medicine Ludwig Maximilian University of Munich  Munich Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leon J.","family":"de Windt","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, Faculty of Health, Medicine and Life Sciences Maastricht University  Maastricht The Netherlands"},{"name":"Faculty of Science and Engineering Maastricht University  Maastricht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. H. 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