Abstract 15247: Caloric Restriction Enhances Cyclic AMP/PKA Axis and Ameliorates Cardiac Remodeling by Restoring Mitochondrial Damage
[Rationale] Caloric restriction (CR) promotes beneficial cardiovascular effects and increases intracellular cyclic AMP levels leading to protein kinase A (PKA) activation and maintain cellular viability by modulating selective mitochondrial autophagy (Nat Cell Biol 2011). We hypothesized that CR may intervene metabolic cardiac remodeling in diabetes through the activation of cyclic AMP/PKA pathway that may link to an autophagy (mitophagy).
[METHODS AND RESULTS] Sixteen-week-old type 2 diabetic KK/Ay mice were allocated into CR (KK-CR) and ad libitum (KK-AL) group. KK-CR exhibited 32.6±1.58% reduction in body weight. Echocardiography revealed that systolic and diastolic function and left ventricular hypertrophy (LVPWd/IVSd; 72.5±0.3/72.5±2.5μm) were improved in KK-CR compared to KK-AL (EF; 72.3±1.7% vs 65.6±2.0%, DcT; 38.8±1.93 msec vs 48.8±1.31 msec, LVPWd/IVSTd=72.5±0.3/72.5±2.5μm vs 92.5±7.5/85.0±2.9 μm). Interstitial fibrosis was reduced in KK-CR heart (0.45±0.10 fold vs KK-AL). Capillary density was increased (2.05±0.26 fold vs KK-AL) and cardiomyocyte surface area was decreased in KK-CR (0.68±0.08 fold vs KK-AL). Transmission electron microscopy revealed decline in the fragmented mitochondria in KK-CR (Fig.1). PINK1 and parkin, the cooperative mediators for the damaged mitochondria via mitophagy, were increased in mitochondrial fraction obtained from KK-AL heart extract, but those were restored in KK-CR. Cyclic AMP/PKA activity and autophagy (assessed by LC3 turnover assay) of each heart extract were enhanced in KK-CR. Isoprotelenol (10 μM) and 8-bromo-cyclic AMP (1 mM) increase autophagy of cultured neonatal cardiomyocyte, which is abrogated by PKA antagonist H-89 (10 μM) or RNA interference to ablate the catalytic subunits of PKA Cα and Cβ.
[CONCLUSION] CR ameliorates metabolic cardiac dysfunction and mitochondrial remodeling by enhancing the cyclic AMP/PKA axis through an autophagic activation.
- Cell signaling
- Mitochondrial energetics, heart failure, arrhythmias
- Ventricular remodeling
- © 2011 by American Heart Association, Inc.