Abstract 487: Promotion of Chip-Mediated P53 Degradation Protects the Heart from Ischemic Injury
Accumulation of a tumor suppressor protein p53 in the myocardium mediates the transition from adaptive cardiac hypertrophy to heart failure. However, the mechanism of p53 accumulation in the heart and its therapeutic implications have been elusive. Here we show that downregulation of a chaperon-associated E3 ubiquitin ligase CHIP (carboxyl terminus of Hsp70-interacting protein) mediates hypoxia-induced p53 accumulation in the heart and that promotion of CHIP-induced p53 degradation protects the heart from ischemic injury. Under physiological conditions, CHIP limited the amount of p53 protein at low levels by inducing proteasomal degradation of p53. Under hypoxic conditions, hypoxia inducible factor-1 (HIF-1) downregulated CHIP, leading to p53 accumulation. Overexpression of CHIP or administration of 17-AAG, a geldanamycin derivative that inhibits Hsp90 and induces the degradation of CHIP client proteins, promoted CHIP-mediated p53 degradation and attenuated ischemic cardiac injury. These results indicate that CHIP is a crucial regulator of p53 accumulation in ischemic hearts and suggest that promotion of CHIP-mediated p53 degradation is a novel therapeutic strategy for heart diseases.