Fatty acid metabolism is essential to maintain energetics and function in the normal heart. However, alterations in metabolism, energetics, and dysfunction have been documented in pathological hypertrophy and heart failure. These metabolic changes are consistent with an increased reliance on glucose and lactate at the expense of fatty acids, representing a reversion to a fetal metabolic profile. As the progression of heart failure continues, energy deprivation, as a result of declining ATP production from fatty acids, becomes a limiting factor in the ability of the failing heart to sustain normal function. Although the mechanisms are elusive, it appears that key metabolic enzymes that regulate fatty acid metabolism are downregulated. Therefore, it is conceivable that restoration of fatty acid oxidation may be beneficial for the failing heart. The function acetyI CoA carboxylase 2 (ACC2) is to catalyze the formation of malonyl CoA from acetyl CoA. As malonyl CoA levels rise, fatty acid transport through carnitine palmitoyl transferase I (CPTI) is inhibited. Therefore, ACC2 may be a potential target in which to modify fatty oxidation through its action on malonyl CoA. Previous studies established that the ACC2 total knockout mouse demonstrated increased fatty acid oxidation with a concurrent reduction in malonyl CoA in cardiac tissue. Therefore, the purpose of the present study is to enhance cardiac fatty acid oxidation by targeting ACC2 in a mouse model. The specific hypothesis of this study is that the increased fatty acid oxidation accompanied by ACC2 deletion will sustain mitochondrial function and myocardial energetics in hypertrophied hearts, thus protecting from the transition to heart failure. The results of this study will address a critical question in the field of cardiac metabolism and may provide insight to the pharmacological intervention with ACC2 inhibitors for heart failure patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F10-H (21))
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Meadows, Tawanna
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University of Washington
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