Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy

Chathurika Henpita, Rajesh Vyas, Chastity L Healy, Tra L Kieu, Aditi U. Gurkar, Matthew Yousefzadeh, Yuxiang Cui, Aiping Lu, Luise Angelini, Ryan O'Kelly, Sara J Mcgowan, Sanjay Chandrasekhar, Rebecca R. Vanderpool, Danielle Hennessy-Wack, Mark A. Ross, Timothy N. Bachman, Charles McTiernan, Smitha P.S. Pillai, Warren Ladiges, Mitra LavasaniJohnny Huard, Donna Beer-Stolz, Claudette M. St. Croix, Simon C. Watkins, Paul D. Robbins, Ana L. Mora, Eric E. Kelley, Yinsheng Wang, Timothy D. O'Connell, Laura J. Niedernhofer

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1−/D mice). Ckmm-Cre+/−;Ercc1−/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre+/−;Ercc1−/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre+/-;Ercc1−/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre+/−;Ercc1−/fl and Ercc1−/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.

Original languageEnglish (US)
Article numbere13782
JournalAging cell
Issue number4
StatePublished - Apr 2023

Bibliographical note

Funding Information:
We are grateful to the staff of the Research Animal Resources at UMN and the Animal Research Center at Scripps Research Institute, Florida. We are also grateful to Elizabeth Thompson and George Roy at UMN, who analyzed the SNPs in ERCC1, ERCC4, and ERCC5 for association with cardiovascular disease. We are grateful to Megan Riddle at UMN, who performed p53 immunofluorescent staining in heart samples.

Funding Information:
Funding for this project came from the NIH: P01 AG043376 (PDR, LJN, YW, EEK, DBS, CMS, SCW, WLL), K99‐R00 AG049126 (AUG), R56 AG059676, R01 AG063543, P01 AG062413 (PDR, LJN), P20 GM109098 and AHA 19TPA34850089 (EEK), R24 AG047115 (WLL) and P01 HL103455‐06 (ALM), NSF 1359369 (SC), Irene Diamond Fund/AFAR Postdoctoral Transition Award (MJY), The Institute for Transfusion Medicine and The Hemostasis and Vascular Biology Research Institute phenotyping core (ALM). R01 HL130099 and R01 HL152215 (TDO). The Jabilain Family Foundation provided philanthropic support for research in cardiology to Scripps Research Institute, which supported this project.

Publisher Copyright:
© 2023 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.


  • cardiomyopathy
  • congestive heart failure
  • genotoxic stress
  • oxidative stress


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