Abstract 183: Branched-Chain Amino Acid Catabolic Reprogramming in Heart Failure

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Abstract

Abnormal branched-chain amino acids (BCAA) catabolism has been strongly linked with cardiovascular and metabolic diseases in recent studies. In heart, metabolic reprogramming associated with the onset of heart failure has been established based on fetal-like changes in fatty acid and glucose metabolism, while little is known about the changes in amino acid homeostasis. In this report, we demonstrated a signature of suppressed BCAA catabolism in failing rodent and human hearts. The branched-chain α-keto acids (BCKA), intermediate of BCAA catabolism, accumulates, closely coordinated with reduced expression of key enzymes of BCAA catabolism in pathologically stressed myocardium. The down-regulation of these genes mimics a similar expression pattern observed in neonatal heart, indicating a fetal-like genetic reprogramming. Using both in vitro and in vivo models, we identified KLF15 as a key transcriptional regulator of the BCAA catabolic circuitry in heart. Genetic inactivation of BCAA catabolic pathway resulted in elevated cardiac BCKA levels and promoted cardiac dysfunction in response to mechanical overload, associated with increased oxidative stress and impaired mitochondrial respiration. Taken together, our data established for the first time that BCAA catabolic reprogramming is an integral component of metabolic remodeling that contributes to heart failure progression.

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