R. Tian, M.D.,Ph.D.
Myocardial energetics is impaired and fatty acid oxidation decreased in failing hearts of both animal models and patients. Although it is increasingly recognized that altered cardiac energy metabolism is integral to the development and progression of heart failure, optimizing metabolism of the failing heart has proven to be a challenge as the mechanisms linking abnormal metabolism to contractile dysfunction in heart failure remain poorly understood. Fatty acids are the primary fuel of the adult heart; impaired fatty acid oxidation (FAO) can be maladaptive as it reduces the mitochondrial capacity for ATP synthesis. Furthermore, decreased FAO under conditions of increased fatty acid availability such as obesity, metabolic syndrome or high sympathetic activity can lead to accumulation of active lipid metabolites in myocardium causing lipotoxicity. As PPARa, a master transcription factor for multiple FAO enzymes, was downregulated in cardiac hypertrophy and failure, previous studies aimed at normalizing fatty acid utilization in failing hearts have sought to reactivate PPARa. These studies yielded very mixed results. Genetic and short-term pharmacological activation of PPARa resulted in lipotoxic cardiomyopathy, contractile dysfunction and impaired response to myocardial ischemia, while studies using chronic PPARa activators showed no effect in cardiac remodeling. Since PPARa regulates many aspects of fatty acid metabolism ranging from uptake, activation to β-oxidation; it is likely that over-activation of fatty acid uptake that exceeds oxidation capacity can lead to lipotoxicity. To date, it has not been tested whether strategies that specifically enhance fatty acid oxidation in mitochondria or decrease active lipid intermediates in the cytosol improves the outcome of heart failure. Therefore, we propose to enhance fatty acid entry into mitochondria via muscle carnitine palmitoyl transferease-1 (mCPT-1), the rate-limiting step of long chain fatty acid oxidation, by lowering malonyl-CoA level in the heart. This will be achieved by genetic deletion of the enzyme that catalyzes malonyl-CoA formation: acetyl-CoA carboxylase 2 (ACC2). We will apply this strategy in non-obese and obese mouse models subjected to pressure overload induced heart failure. Myocardial energy metabolism and mitochondrial function in these hearts will be assessed by multi-nuclear NMR spectroscopy and biochemical assays at baseline, compensated hypertrophy, and heart failure.