Abstract 15269: Knockout of the Energy Sensing AMP Kinase Disengages Akt Deletion-Conferred Cardioprotection Against Obesity Cardiomyopathy
Obesity, type 2 diabetes mellitus and other features of metabolic syndrome are major risk factors for cardiovascular diseases. Akt and AMPK are two vital signaling molecules participating in the maintenance of cardiac homeostasis. Our earlier study reported that Akt2 knockout attenuates obesity-induced cardiomyopathy although the underlying mechanism remains elusive. We hypothesize that intact energy sensing AMPK signaling is essential to Akt knockout-offered protection against obesity. This study was designed to evaluate the impact of AMPK knockout on Akt2 knockout-offered cardioprotection against fat diet-induced obesity. Cardiac function was evaluated in wild type (WT), Akt2 knockout (Akt KO), AMPK knockout (AMPK KO) and double knockout (DKO, F5-6) mice fed a low (10% calorie) or high (45% calorie) fat diet for 5 mo. High fat diet consumption resulted in elevated body and heart weights in WT mice, Akt KO and DKO attenuated high fat diet-induced body weight gain. Akt KO alleviated fat diet-induced heart weight gain, the effect of which was nullified in DKO mice. Echocardiography displayed a rise in wall thickness, left ventricular end diastolic diameter, left ventricular end systolic diameter and a decrease in fractional shortening following high fat diet intake in WT, all of which were significantly attenuated by Akt KO. Interestingly, DKO cancelled off Akt2 knockout-induced beneficial effect. Along the same line, Akt2 KO prevented high fat diet-induced changes in cardiomyocyte anomalies including decreased peak shortening, maximal velocity of shortening and relengthening as well as prolonged relengthening, the effect of which was cancelled off by DKO. DKO resulted in a further impairment of cardiac contractile function following high fat diet intake. Furthermore, high fat diet intake resulted in a more pronounced increase in cardiomyocyte cross sectional area and hypertrophic proteins ANP and GATA4 in DKO mice. Western blot analysis of autophagy markers revealed that fat diet intake impaired autophagy flux, the effect of which was reconciled and accentuated by Akt2 KO and DKO, respectively. Taken together, our data revealed that AMPK plays an essential role in Akt knockout offered cardioprotection through preservation of autophagy flux.
- © 2013 by American Heart Association, Inc.