Abstract 543: Uncovering the Mechanisms by Which Fatty Acid Oxidation Suppresses Cardiomyocyte Hypertrophy

In cardiac hypertrophy, the adult heart switches from mainly using fatty acids to an increased reliance on glucose to maintain its energetic demands. We have previously shown that preserving fatty acid oxidation (FAO) by cardiac-specific deletion of Acetyl-CoA Carboxylase 2 (ACC2) prevents the shift of substrate preference towards glucose, preserves cardiac function and reduces cardiomyocyte hypertrophy during chronic pressure overload. To determine whether maintaining FAO specifically prevented cardiomyocyte hypertrophy, we treated adult rat cardiomyocytes (CMs) with and without adenoviral-mediated ACC2 knock-down (KD) with phenylephrine (PE, 10 μM). ACC2 KD effectively prevented CM hypertrophy after PE stimulation compared to control CMs (+9±6% vs. 42±6%) in medium supplemented with fatty acids (FA) (5.5 mM glucose, 0.4 mM mixed long-chain FAs and 0.1 mU/ml insulin). Whereas PE stimulation in control CMs increased glucose uptake (+28±8%), accumulation of glycolytic intermediates and lactate (+52±15%), this was normalized after ACC2 KD. Inhibiting FAO by etomoxir or increasing glucose utilization by dichloroacetate abolished the antihypertrophic effects of ACC2 KD after PE stimulation. However, replacing glucose with pyruvate or propionate restored the anti-hypertrophic effect of ACC2 KD. The expansion of TCA cycle pool caused by PE stimulation was also suppressed by ACC KD. Furthermore, ACC2 KD resulted in decreased intracellular amino acid levels, consistent to what has been seen in ACC2 knock-out hearts in vivo. This was accompanied by reduced glutamine consumption from the media (-60±25%) in ACC2 KD CMs, indicating reduced glutamine reliance. Taken together, our data suggest that ACC2 KD reduces the utilization of glucose and glutamine; both substrates known to be required for cell growth in vitro and in vivo. This further supports the hypothesis that maintaining FAO prevents the metabolic switch and CM hypertrophy.