Repressor Activator Protein 1 Worsens Cardiomyopathy in Diet-induced Type 2 Diabetic Mice

Background Diabetic cardiomyopathy is defined by the structural and functional abnormalities of the myocardium in the absence of other cardiac risk factors in diabetic patients. In diabetes, the increment of fatty acid metabolism and subsequently cardiac inefficiency and myocardial lipid accumulation may underlie the pathology of diabetic cardiomyopathy. The telomeric protein repressor activator protein 1 (Rap1) is an identified regulator that regulates gene transcription by binding to non-telomeric sites. In particular, Rap1 can bind to nuclear PPARα (an important transcriptional regulator of lipid metabolism) loci, and regulate transcription of PPARα and its target genes, including CD36 (fatty acid transporter). However, the effects of Rap1 on diabetic cardiomyopathy are largely unknown. Thus, the present study investigated if Rap1 deficiency protects against diabetic cardiomyopathy and explored the underlying mechanisms. Methods and Results High fat diet feeding is a widely used protocol to induce type 2 diabetes in mice. Upon high fat feeding (60% fat) for 12 weeks, male Rap1 knockout (KO) mice displayed significantly reduced body weight gain compared with their wild type (WT) littermates. The glucose tolerance test and insulin tolerance test showed that Rap1 deficiency in the high fat diet fed-mice led to improved glucose intolerance and insulin action. Furthermore, Rap1 deficiency attenuates high fat diet-induced cardiac structural remodeling and dysfunction in mice, as evidenced by significantly reduction in left ventricular internal dimension in systole (LVIDs), left ventricular mass, increment in ejection fraction (EF) and fractional shortening (FS), as well as improving of myocardial performance index (MPI). These changes were associated with remarkable reductions in the mRNA and protein expression of PPARα and CD36 in the myocardium of high fat fed-Rap1 KO mice, indicating that Rap1 deficiency may protect against diabetic cardiomyopathy via the suppression of PPARα/CD36 signaling. Conclusion In summary, these results suggest that Rap1 impairment has cardioprotective consequences in the high fat diet-induced diabetes model, identifying a new dimension in the roles of endogenous Rap1. Support or Funding Information The authors’ work was supported by The General Research Fund (17117217M, 17123718M, Research Grants Council of Hong Kong) and The National Natural Science Foundation of China (No. 81800245).