NMR of Mitochondrial Transporters in Cardiac Hypertrophy

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DESCRIPTION (provided by applicant): The overall objective of the proposed research is to elucidate and counter inefficiencies in fatty acid and carbohydrate metabolism for energy production, imposed by compensatory recruitment of alternative pathways and altered metabolic gene expression in pressure overloaded hearts. Aims are intended to yield new metabolic strategies to mitigate the development of cardiomyopathy leading to overt heart failure. Ongoing work has elucidated 1) increased NADPH-dependent malic enzyme (ME) expression in cardiac hypertrophy that increases anaplerotic flux into the second span of the TCA cycle and may impact on regulation of fatty acid oxidation and storage, with apparent effects on contractility; 2) increased expression of the liver (L) isoform of carnitine palmitoyltransferase I (L-CPT1) in hypertrophied hearts that coincides with reduced fatty acid oxidation; 3) large reductions in both content and turnover rates of the triacylglyceride (TAG) pool in hypertrophied hearts that coincide with a loss of the contribution from TAG to fatty acid oxidation. Based on these key findings of the current funding period, experiments test the hypothesis that normal TAG content and turnover are required to maintain baseline lipolytic contributions to fatty acid oxidation, which is critical to the flexibility of the metabolic support of contractility, and that dysregulation of lipid storage dynamics in cardiac hypertrophy, in part, due to maladaptive shifts in anaplerosis via malic enzyme and fatty acid oxidation via L- CPT1, affects the metabolic efficiency of contraction. The hypothesis will be tested using dynamic-mode 13C NMR of genetically altered rat hearts and transgenic mouse hearts with pressure overload hypertrophy. Aim 1 investigates the effects of increased ME expression on both triglyceride dynamics and redox regulation in hypertrophied rat hearts using adenoviral-based ME overexpression in normal hearts and RNA suppression of ME in hypertrophy. This aim also tests the effects of fatty acid chain length and dietary fat on TAG dynamics in cardiac hypertrophy and the metabolic fate of pyruvate due to differential ME expression. Aim 2 tests the functional significance of increased L-CPT1 expression on the reciprocal activity and balance between fatty acid storage kinetics and oxidation in hypertrophied rat hearts using L-CPT1 RNA inhibition. Aim 3 explores the influences of augmented fatty acid uptake and PPAR1 expression on the changes in TAG dynamics and oxidation in hypertrophied hearts of transgenic mice with either fatty acid transporter 1 (FATP1) overexpression or low overexpression of PPAR1. Rather than investigate a single enzyme, we propose an integrative approach to investigate potentially maladaptive changes in metabolic enzyme expression in cardiac hypertrophy, while exploring the potential mechanisms for, and functional significance of reduced TAG dynamics in hypertrophy. The anticipated findings will contribute a basic, mechanistic understanding to a topical problem of clinical importance, which is the link between dysregulation of cardiac lipid dynamics and contractile dysfunction in the pathogenesis of decompensated hypertrophy.