Intact DNA Repair in Differentiated Cardiomyocytes is Essential for Maintaining Cardiac Function in Response to Physiological Stimulus

Abstract

IntroductionDNA in every cell is continuously damaged and DNA repair mechanisms are essential for protection against DNA damage‐induced aging‐related diseases. Evidence indicates that DNA damage is associated with heart failure. We have shown that unrepaired endogenously generated DNA damage drives the early onset of progressive heart failure (de Boer et al. Cardiovasc Res, 2018;114:S105). Here we studied the effects of a physiological stimulus on cardiac function in a mouse model with deficient DNA repair.MethodsTo increase the burden of spontaneous DNA damage, we generated mice with cardiomyocyte‐restricted inactivation of DNA repair endonuclease XPG (αMHC‐Xpgc/−). To induce physiological left ventricular (LV) hypertrophy, mice were exposed to 11 weeks of voluntary wheel running. Subsequently, LV geometry, function and structure were studied at age 16 weeks.ResultsCardiomyocyte‐restricted inactivation of Xpg resulted in systolic as well as diastolic LV dysfunction, demonstrated by decreases in fractional shortening, LVdP/dtP40 and LVdP/dtmin and increases in LV end‐diastolic lumen diameter (LVEDD) and relaxation time constant tau compared to WT (Table). In addition, expression level of hypertrophy maker gene β‐myosin heavy chain (β‐MHC) was elevated. Physical activity has been shown to be beneficial for maintaining and improving cardiac function in mice after myocardial infarction (de Waard et al. Circ Res, 2007;100:1097). In contrast, exercise failed to ameliorate LV remodeling and dysfunction in αMHC‐Xpgc/−, as it produced further increases in LVEDD, tau and β‐MHC compared to sedentary αMHC‐Xpgc/− (Table). Moreover, myocardial collagen content and the number of γH2A. X positive nuclei, a marker for DNA damage, were increased, suggesting that αMHC‐Xpgc/− showed increased susceptibility to exercise.ConclusionCardiomyocyte‐restricted loss of DNA repair protein Xpg increases cardiac vulnerability to develop heart failure in response to exercise training. These findings underscore the importance of genomic stability for maintenance of cardiac function, not only during basal conditions, but also in response to a physiological stimulus.Support or Funding InformationSupported by a NHF Grant 2007B024 and CVON‐ARENA (CVON2011‐11).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.