Intact DNA Repair in Differentiated Cardiomyocytes Is Essential for Maintaining Cardiac Function in Response to Pressure Overload in Mice

Introduction: DNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage-induced aging-related diseases. For example, deficient repair of endogenously generated DNA damage in mice with cardiomyocyte-restricted inactivation of Xpg, is associated with progressive heart failure (de Boer et al. Aging Cell 2023). Here we tested the hypothesis that unrepaired DNA damage in differentiated cardiomyocytes increases cardiac vulnerability in response to hemodynamic overload. Methods: At 8 weeks of age, αMHC-Xpgc/- and control (Ctrl) mice were subjected to pressure overload by mild transverse aortic constriction (TAC). Eight weeks after TAC, left ventricular (LV) function was assessed using echocardiography and hemodynamic measurements, followed by histological and molecular analyses. Results: Cardiomyocyte-restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction. TAC-induced LV hypertrophy was similar in both groups (Ctrl 38%; αMHC-Xpgc/- 34%). In Ctrl mice, LV hypertrophy was accompanied by minimal LV dilation and only modest changes in systolic and diastolic LV function. Conversely, TAC in αMHC-Xpgc/- produced severe LV dilation and dysfunction and resulted in overt backward failure, demonstrated by marked increases in LV end-diastolic pressure, left atrial weight and lung fluid weight. These changes were accompanied by further increases in the expression levels of the hypertrophic marker genes atrial natriuretic peptide and beta-myosin heavy chain. Moreover, lectin staining revealed a decrease in capillary density and TUNEL staining revealed further elevated levels of myocardial apoptosis in αMHC-Xpgc/--TAC mice as compared to Ctrl-TAC mice. In addition, a significant increase of myocardial collagen content was observed in αMHC-Xpgc/--TAC but not in Ctrl-TAC mice. Conclusion: Cardiomyocyte-restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to pressure-overload. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only under basal conditions, but also during increased cardiac loading conditions. Supported by the Dutch Heart Foundation [Grants 2017B018-ARENA-PRIME; 2021B008-RECONNEXT]. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.