Loss of Repressor Activator Protein 1 Precipitates Cardiac Aging in Mice via p53/PPARα Signaling

Abstract

BackgroundTelomere dysfunction has been linked to many aspects of the aging process. Increasing evidence indicates that telomere dysfunction leads to cardiac mitochondrial defects. Mammalian repressor activator protein 1 (Rap1) is one of the components of shelterin complex and essential for the maintenance of telomere length and structural integrity. Our preliminary work showed that aged Rap1 knockout (Rap1−/−) mice exhibited more pronounced aging‐associated phenotypes (including earlier hair graying, hair loss, reduced body weight). However, the effects of Rap1 on mitochondrial function and its contribution to cardiac aging are largely unknown. Thus, the present study investigated whether or not loss of Rap1 in mice precipitates cardiac aging and explored the underlying mechanisms.Methods and ResultsMice cardiac function was assessed with transthoracic echocardiography performed noninvasively using a Vevo 2100 high‐resolution imaging system. Deletion of Rap1 in mice aggravated aging‐related cardiac structural changes and dysfunction, as evidenced by increased left ventricular (LV) posterior wall end‐diastole and LV mass, reductions in ejection fraction and fractional shortening, as well as significantly reduced myocardial performance index (all p < 0.05, Rap1−/− vs. age‐matched counterparts). These changes were associated with greater cardiac senescence (enhanced SA‐β‐gal staining), cardiac hypertrophy (enhanced wheat germ agglutinin staining and increased the ratio of heart weight with body weight), abnormalities in the mitochondrial ultrastructure (cristae fragmentation, vacuolization). Mechanistically, Rap1 deficiency led to shorter telomere (T/S ratio), enhanced DNA damage (γH2AX) and increased nuclear p53 level in vivo in the myocardium and in primary cardiomyocytes when compared to age‐matched counterparts (one year old). Chromatin immunoprecipitation revealed that p53 directly binded to the promote site of PPARα [a central regulator of cardiac fatty acid metabolism (FAM)] and repressed its expression. Rap1 deficiency impaired FAM (reduced CD36, CPT1α, ACADL level and palmitate‐induced oxygen consumption), while PFTα (a p53 inhibitor, i.p. 1.1 mg/kg/day) treatment in Rap1−/− mice significantly alleviated cardiac aging and enhanced FAM by restoration of PPARα.ConclusionsWith aging, Rap1 deficiency may lead to shorter telomere length, increase DNA damage and thereby activate p53, which in turn suppresses PPARα, leading to impaired FAM and mitochondrial defects with abnormal cardiac structure and dysfunction. These findings may identify a new cardiac dimension in the physiological role played by telomere‐Rap1.Support or Funding InformationThe authors’ work was supported by the General Research Fund (17123718M, Research Grants Council of Hong Kong).