Abstract 273: p53 Shifts the Balance of Energy Source in Cardiac Myocytes
Altered energetics play an important role in the mechanism of heart failure. We have previously demonstrated mitochondrial respiration is dose-dependently regulated by p53 in both human cancer cells and mice. Functionally, this translates to a profound reduction in exercise capacity of p53-deficient mice. However, the role of p53 in cardiac metabolism is unknown. We examined the effect of p53 on cardiac energetics. Neonatal rat cardiac myocytes were prepared to examine the metabolism under the induction of p53. p53 was induced and oxygen consumption was augmented after the treatment with nutlin-3 (MDM2 inhibitor). The activation of p53 reduced glucose utilization and lactate production. To examine the pathological effect of p53 in the heart, myocytes were exposed to hypoxia. Hypoxia induced the accumulation of p53 and increased the percentage of apoptotic myocytes in a time dependent manner. (3hrs: 7.4±0.6%, 6hrs:13±2.7%,12hrs: 20.1±2.8%). At the early stage of hypoxia, the ratio of Bax/bcl-2 protein was unchanged, while glycolysis was inhibited with the accumulation of p53. Inhibition of p53 by the treatment with pifithrin α (PFTα) recovered glycolysis, and reduced apoptosis (cont: 13±2.2%, PFTα: 8.2±1.2% at 6hrs). Although p53 did not affect the level of ATP, phosphocreatine was significantly preserved by the inhibition of p53. Expression of TIGAR (TP53-induced glycolysis and apoptosis regulator) protein was increased with the activation of p53 in hypoxic myocytes. Enzyme assay revealed that the level of fructose-2,6-bisphosphate (Fru-2,6-P2) was decreased after the induction of p53 and TIGAR. Since TIGAR protein is reported to decrease Fru-2,6-P2 and inhibit the key glycolytic enzyme, 6-phosphofructo-1-kinase (PFK-1), our results suggest that p53 inhibits glycolysis via TIGAR in hypoxic myocytes.Therefore p53 accumulation inhibits glycolysis and deteriorates the energetics of the myocytes, which in turn increases apoptosis. Altering the balance of energy source by inhibiting p53 preserves the high energy phosphates and protects myocytes. p53 is a new target to improve the cardiac metabolism.