Deletion of Telomere‐Rap1 aggravates cardiac aging by impairing fatty acid oxidation via PPARα signaling

Abstract

The heart undergoes multiple functional and structural declining with aging, including impaired fatty acid metabolism, cardiac dysfunction and hypertrophy. Repressor activator protein 1 (Rap1) as a component of shelterin complex is essential for the maintenance of telomere function. Moreover, Rap1 also regulates gene transcription by binding to non‐telomeric sites such as the nuclear hormone receptor ‐ peroxisome proliferator‐activated receptor α (PPARα) which plays a central role in the cardiac fatty acid metabolism and mitochondrial function. However, it's still not clear whether or not the heart of Rap1−/− mice also suffers more aging associated disorders. Thus, the present study aims at the role of Rap1 in cardiac aging and its possible mechanism. Echocardiography showed enlarged left ventricular internal dimension (LVID) and LV mass, which suggested dilated hypertrophy, and elevated myocardial performance index (MPI) in Rap1−/− mice at age of 85weeks, indicating systolic and diastolic dysfunction (all P<0.05 vs. Rap1+/+). The greater adverse cardiac remodeling in aged Rap1−/− mice was paralleled by elevated cardiomyocyte area showed by Wheat germ agglutinin (WGA) staining (P<0.05 vs. Rap1+/+). p53 as a senescence marker was also increased indicating more severe cellular senescence in cardiomyocyte of Rap1−/− mice (P<0.05 vs. Rap1+/+). From apex cordis of Rap1 wildtype and knockout mice, electron microscopy showed more enlarged pleomorphic mitochondria containing cristae fragmentation, vacuolization and disrupted external membranes in aged Rap1 knockout mice compared to age‐matched wildtype counterparts. Decreased Acetyl‐CoA carboxylase (ACC) (catalyzes the production of malonyl‐CoA) and Elevated Carnitine palmitoyl transferase I (CPT‐1) (transports fatty acyl‐CoA into mitochondria) and Acyl‐CoA dehydrogenase long chain (ACADL, catalyzes most of fatty acid β‐oxidation) were detected in aged Rap1 knockout mice(all P<0.05 vs. Rap1+/+), indicating Rap1 deficiency may lead to reduced fatty acid oxidation during aging. In the heart of aged Rap1−/− mice, PPARα was reduced compared with age‐matched wildtype counterparts (P<0.05 vs. Rap1+/+), suggesting that with aging, Rap1 may down‐regulate PPARα signaling in the heart and control fatty acid metabolism resulting in cardiac dysfunction and hypertrophy. In conclusion, Rap1 deficiency may impair myocardial fatty acid oxidation via PPARα signaling, leading to more severe cardiac aging as cardiac dysfunction and hypertrophy. These findings may identify a new extratelomeric role of Rap1 in cardiac metabolism during aging.Support or Funding InformationThe authors' work was supported by the Health and Medical Research Fund (04151816, Hong Kong) and General Research Fund (17121315M, 17123915M and 17117217M, Research Grants Council of Hong Kong).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.