Abstract 16484: Maintaining Cardiac Fatty Acid Oxidation in Pressure-Overload Hypertrophy Preserves Function and Energetics
The reversion to the fetal metabolic profile in the hypertrophied heart is well documented, although whether this shift is adaptive or maladaptive is still questioned. Since malonyl CoA production via acetyl CoA carboxylase 2 (ACC2) inhibits mitochondrial fatty acid transport, we hypothesized that mice with a cardiac-specific deletion of ACC2 (ACC2H-/-) would maintain cardiac fatty acid oxidation (FAO) and have improved function and energetics in pathological hypertrophy. ACC2 deletion was confirmed with Western blotting and resulted in ∼50% reduction of malonyl CoA levels. Isolated perfused hearts of ACC2H-/- mice demonstrated similar contractile performance with ∼60% increase in the relative contribution of fatty acids to oxidative metabolism (FAO) as compared to controls (Con; 67±5% vs 41±3%, p<0.01). After 8 weeks of pressure-overload via transverse aortic constriction (TAC), substrate utilization in ACC2H-/- was similar to sham animals, while Con-TAC exhibited ∼50% decrease in FAO (P<0.01) and ∼50% increase in glucose oxidation (P<0.001). Significant increases in glycolytic end products (lactate/alanine) and anaplerosis were also seen in Con-TAC; this was abolished in ACC2H-/--TAC. Global metabolic profiling, assessed by GCxGC-TOFMS, showed metabolite changes in Con-TAC that did not appear in ACC2H-/--TAC. Furthermore, cardiac energetics, assessed by 31P NMR spectroscopy, and cardiac function, assessed by echocardiography, were maintained in ACC2H-/--TAC. Importantly, ACC2H-/--TAC developed ∼25% less cardiac hypertrophy (P<0.05) and ∼45% less fibrosis compared to Con-TAC (P<0.01). In summary, maintaining mitochondrial FAO during the development of cardiac hypertrophy leads to preserved cardiac function, energetics, and an attenuation of hypertrophic growth and fibrosis. These data suggest that reversion to the fetal metabolic profile in the setting of pressure-overload is maladaptive and maintenance of the inherent cardiac metabolic profile and mitochondrial oxidative capacity should be the focus of therapeutic strategies.
- © 2011 by American Heart Association, Inc.