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

Martine de Boer, Maaike te Lintel Hekkert, Jiang Chang, Bibi S. van Thiel, Leonie Martens, Maxime M. Bos, Marion G.J. de Kleijnen, Yanto Ridwan, Yanti Octavia, Elza D. van Deel, Lau A. Blonden, Renata M.C. Brandt, Sander Barnhoorn, Paula K. Bautista-Niño, Ilona Krabbendam-Peters, Rianne Wolswinkel, Banafsheh Arshi, Mohsen Ghanbari, Christian Kupatt, Leon J. de WindtA. H.Jan Danser, Ingrid van der Pluijm, Carol Ann Remme, Monika Stoll, Joris Pothof, Anton J.M. Roks, Maryam Kavousi, Jeroen Essers, Jolanda van der Velden, Jan H.J. Hoeijmakers, Dirk J. Duncker

Research output: Articles / NotesScientific Articlepeer-review

7 Scopus citations

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 languageEnglish
Article numbere13768
JournalAging Cell
Volume22
Issue number3
DOIs
StatePublished - Mar 2023
Externally publishedYes

Keywords

  • apoptosis
  • cardiac function
  • congestive heart failure
  • DNA damage
  • DNA repair

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