Abstract 14468: Carolic Restriction Ameliorates Cardiac Steatosis by Activation of Autophagy via Cyclic AMP/AMPK/PKA Axis
[INTRODUCTION] Cardiac steatosis promotes cardiac remodeling and impair cardiac function due to myocardial lipid accumulation and lipotoxic injury in animals and patients with metabolic disorder. In adipocytes, stimuli that increase intracellular cyclic AMP (cAMP) accelerate lipolysis via AMP-activated protein kinase (AMPK) activation. Caloric restriction (CR) increases intracellular cAMP levels and AMPK activity leading to enhanced autophagic activation (Nat Cell Biol 2011).
[HYPOTHESIS] We assessed the hypotheses that cardiac steatosis may be reversed by CR via activation of autophagy through the cyclic AMP/AMPK axis. [METHODS] High-fat diet-induced obese mice (DIO) and age-matched counterparts fed with normal chow (CTL) were allocated into CR and ad libitum (AL) group.
[RESULTS] Echocardiography revealed that DIO-AL exhibited reduced systolic left-ventricular (LV) function [EF(%); 66.2±2.9 (DIO-AL) versus 76.8±2.3 (CTL-AL)] and LV wall thickening [LVPWd (mm); 0.93±0.08 (DIO-AL) versus 0.73±0.03 (CTL-AL)]. DIO-CR exhibited 32.6±1.58% reduction in body weight. CR reversed the systolic dysfunction [EF (%); 72.3±1.7 (DIO-CR)] and LV hypertrophy [LVPWd (mm); 0.81±0.06 (DIO-CR)]. DIO-AL exhibited enhanced interstitial fibrosis, which was reduced in DIO-CR (0.58±0.10-fold versus DIO-AL). Oil-red-O staining revealed that CR ameliorated the excess of cardiac lipid accumulation observed in DIO-AL. CR reduced cardiac oxidative stress detected by DHE staining. Cardiac autophagy (assessed by LC3 turnover, p62 levels) and cyclic AMP/AMPK activity were enhanced in DIO-CR. The levels of PINK1 and parkin, the cooperative authophagic mediators for damaged mitochondria, were increased in DIO-AL that were reversed in DIO-CR. Nutritional depletion and forskolin treatment enhanced autophagy in cultured cardiomyocytes that was reversed by AMPK inhibition (compound C and siRNA).
[CONCLUSIONS] CR ameliorates cardiac dysfunction and remodeling observed in cardiac steatosis via autophagic activation through the cyclic AMP/AMPK axis leading to the reduction of lipid accumulation and resultant oxidative stress.
- © 2012 by American Heart Association, Inc.