Abstract 13634: Re-Activation of Autophagic Flux by Akt2 Knockout is Beneficial for Cardiac Function in High Fat Diet-Induced Obesity
Background High fat diet (HFD)-induced obesity is a major risk for the development of cardiometabolic syndrome, but the underlying mechanisms are still elusive. Although the role of autophagy has been consolidated in various cardiovascular diseases and in non-cardiac tissues in obesity, its role in the onset and development of obese cardiomyopathy is still unclear. This study was designed to test the hypothesis that HFD interrupts cardiac autophagic flux and therefore reactivation of autophagic flux using Akt2 knockout should be protective against cardiac dysfunction in HFD-induced obesity.
Methods Wild type mice and Akt2 knockout (Akt2−/−) mice were fed a low fat diet (LFD) or HFD for 5 months. Echocardiographic, cardiomyocyte mechanical function [peak shortening (PS), time-to-PS, time-to-90% relengthening (TR90)], and intracellular calcium handling were assessed. Morphological changes were evaluated using H&E staining and Masson-Trichrome staining for fibrosis. Western blot and RT-PCR were performed to examine the levels of cell signaling molecules and fetal genes. Transmission electron microscopy (TEM) was employed to monitor subcellular changes within cardiomyocytes.
Results HFD initiated cardiac hypertrophy and contractile dysfunction, which were ameliorated by Akt2−/− as evidenced by echocardiographic, cardiomyocyte contractile and intracellular calcium properties. Morphologically, HFD increased the cross--sectional diameter of cardiomyocytes and fibrosis among the cardiomyocytes but not in Akt2−/− mice. The protective effect of Akt2−/− was associated with the re-activation of the autophagic flux interrupted by HFD. Furthermore, inhibiting the autophagy with 3-methyl adenine blocked the beneficial effect of Akt2−/− against the development of cardiac hypertrophy.
Conclusions Our results demonstrated that the improvement of cardiac function in HFD-induced obesity by Akt2−/− is through re-activation of autophagic flux and may provide a novel approach for the treatment of the cardiomyopathy under obesity and diabetes. Supported by NIH P20 RR016474
- © 2011 by American Heart Association, Inc.