DNA repair in cardiomyocytes is critical for maintaining cardiac function in mice.

Autor: de Boer M; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands., Te Lintel Hekkert M; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands., Chang J; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands., van Thiel BS; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.; Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands., Martens L; Department of Genetic Epidemiology, Institute of Human Genetics, University Hospital Münster, Münster, Germany., Bos MM; Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands., de Kleijnen MGJ; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands., Ridwan Y; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.; Department of Radiotherapy, Erasmus MC, Rotterdam, The Netherlands., Octavia Y; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands., van Deel ED; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands., Blonden LA; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands., Brandt RMC; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands., Barnhoorn S; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands., Bautista-Niño PK; Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands.; Centro de Investigaciones, Fundación Cardiovascular de Colombia- FCV, Bucaramanga, Colombia., Krabbendam-Peters I; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands., Wolswinkel R; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Arshi B; Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands., Ghanbari M; Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands., Kupatt C; I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany.; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.; Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of Munich, Munich, Germany., de Windt LJ; Department of Molecular Genetics, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.; Faculty of Science and Engineering, Maastricht University, Maastricht, The Netherlands., Danser AHJ; Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands., van der Pluijm I; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands., Remme CA; Department of Clinical and Experimental Cardiology, Heart Center, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands., Stoll M; Department of Genetic Epidemiology, Institute of Human Genetics, University Hospital Münster, Münster, Germany.; Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands., Pothof J; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands., Roks AJM; Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands., Kavousi M; Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands., Essers J; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.; Department of Vascular Surgery, Erasmus MC, Rotterdam, The Netherlands.; Department of Radiotherapy, Erasmus MC, Rotterdam, The Netherlands., van der Velden J; Department of Physiology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.; Netherlands Heart Institute, Utrecht, The Netherlands., Hoeijmakers JHJ; Department of Molecular Genetics, Erasmus MC, Rotterdam, The Netherlands.; CECAD Forschungszentrum, Universität zu Köln, Köln, Germany.; Princess Máxima Center for Pediatric Oncology, Genome Instability and Nutrition, ONCODE Institute, Utrecht, The Netherlands., Duncker DJ; Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Erasmus MC, Rotterdam, The Netherlands.
Jazyk: angličtina
Zdroj: Aging cell [Aging Cell] 2023 Mar; Vol. 22 (3), pp. e13768. Date of Electronic Publication: 2023 Feb 08.
DOI: 10.1111/acel.13768
Abstrakt: 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-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, 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 months. 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 ERCC1 and XPG 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-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.
(© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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