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Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy |
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| Authors: | Chathurika Henpita Rajesh Vyas Chastity L Healy Tra L Kieu Aditi U Gurkar Matthew J Yousefzadeh Yuxiang Cui Aiping Lu Luise A Angelini Ryan D 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 Lavasani Johnny 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 |
| Institution: | 1. Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA;2. Department of Biochemistry, Molecular Biology and Biophysics, Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, Minnesota, USA
Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida, USA;3. Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, Minnesota, USA;4. Department of Molecular Medicine, Scripps Research Institute, Jupiter, Florida, USA Division of Geriatric Medicine, Aging Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;5. Department of Chemistry, University of California, Riverside, Riverside, California, USA;6. Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Steadman Philippon Research Institute, Vail, Colorado, USA;7. Division of Cardiology, Heart and Vascular Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;8. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;9. Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;10. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA;11. Department of Comparative Medicine, University of Washington, Seattle, Washington, USA;12. Department of Orthopedic Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Physical Medicine and Rehabilitation, Northwestern University and Shirley Ryan Ability Lab, Chicago, Illinois, USA;13. Center for Biologic Imaging, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Department of Cell Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA;14. Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA Division of Pulmonary, Critical Care and Sleep Medicine, College of Medicine, The Ohio State University, Columbus, Ohio, USA;15. Department of Physiology and Pharmacology, West Virginia University, Morgantown, West Virginia, USA |
| Abstract: | 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. |
| Keywords: | cardiomyopathy congestive heart failure genotoxic stress oxidative stress |