Abstract 20445: Pras40 Prevents Development of Diabetic Cardiomyopathy

Abstract

Introduction: Diabetes is a multi organ disease and diabetic cardiomyopathy can result in heart failure, which is a leading cause of morbidity and mortality in diabetic patients. Defects in mTOR signaling are believed to contribute to metabolic dysfunctions in diabetic liver and hearts, but evidence is missing that mTOR activation is causal to the development of diabetic cardiomyopathy. PRAS40 (Proline Rich Akt Substrate of 40kDa) is a specific component of mTORC1 that interacts with RAPTOR to inhibit mTORC1 kinase activity Methods and Results: The db/db mouse exhibits key characteristics of T2DM, namely hyperinsulinemia, insulin resistance, hyperglycemia, and develops diabetic cardiomyopathy with decreased cardiac function. Selective mTORC1 inhibition in cardiomyocytes from db/db mice in vivo was achieved using PRAS40 delivered via recombinant cardiotropic adeno-associated vector serotype 9 (AAV9) driven by a cardiomyocyte-specific myosin light chain (MLC2v) promoter construct. Myocardial dysfunction was prevented in AAV-PRAS40 treated db/db mice compared to the AAV-Control group, as seen by significantly higher cardiac ejection fraction (EF%), fractional shortening (FS%) measured by serial echocardiography, despite similar increases in body weight, serum glucose levels, and fat deposition in the liver. The effects of PRAS40 were tested in a model of T2DM induced by high fat diet (HFD). AAV-PRAS40 or AAV-Control was injected at 7 weeks of age and mice were fed HFD chow of or standard for an additional 25 weeks. Decreased cardiac function was observed in the HFD control group measured by echocardiography. This preservation of function was associated with decreased left ventricular diastolic dimension (LVID) and improved diastolic function. This phenotype was associated with improved metabolic function, blunted hypertrophic growth, and preserved insulin sensitivity. Conclusions: mTORC1 inhibition with PRAS40 prevents diabetic cardiomyopathy and improves metabolic function in diabetic mice. These findings may open novel avenues for therapeutic strategies using PRAS40 directed against diabetic-related diseases.