Abstract
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.
| Original language | English |
|---|---|
| Article number | e13768 |
| Journal | Aging Cell |
| Volume | 22 |
| Issue number | 3 |
| Early online date | 8 Feb 2023 |
| DOIs | |
| Publication status | Published - Mar 2023 |
Bibliographical note
Funding Information:Alpha-MHC-Cre mice were kindly provided by Johannes Backs (University of Heidelberg, Heidelberg, Germany); floxed Ercc1 mice were kindly provided by David W. Melton (MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, MRC Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK). Molecular imaging was enabled by the use of imaging equipment provided by the Applied Molecular Imaging Erasmus MC facility. We gratefully acknowledge Hans Bosch for the use of the Vevo770 High-Resolution Imaging System (FUJIFILM VisualSonics Inc.), the Core Facility Genomics of the Medical Faculty Münster for performing RNA sequencing and Robert Beurskens, Wies Lommen, Ruud Zaremba, Jennifer Sarikaya and Rene de Vries for their expert technical support.
Funding Information:
This work was supported by the Dutch CardioVascular Alliance: An initiative with financial support of the Dutch Heart Foundation [Grants 2017B018‐ARENA‐PRIME (to L.J.W., J.V. and D.J.D.), 2018B030‐PREDICT2 (to C.A.R.) and 2021B008‐RECONNEXT (to D.J.D.)], Lijf en leven [Grant DIVERS (to J.E.)], National Institute of Health (NIH)/National Institute of Ageing (NIA) [Grant PO1 AG017242 (to J.H.J.H. and J.P.)], European Research Council Advanced Grants [Grants DamAge (to J.H.J.H.) and Dam2Age (to J.H.J.H.)], Dutch Cancer Society [Grant ONCODE (to J.H.J.H.)], Memorabel and Chembridge (ZonMW; to J.H.J.H. and J.P), BBoL (NWO‐ENW; to J.H.J.H.) and the Deutsche Forschungsgemeinschaft [Grant SFB 829 (to J.H.J.H.).
Publisher Copyright:
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.