Abstract 19033: p53-Mediated Decrease in ROS Signal Reduces Mitophagy via Inactivation of Bnip3 to Aggravate Cardiac Damage After Ischemic Injury
Background: Autophagy degrades damaged organelles for quality control. Tumor suppresser protein p53 expanded the area of myocardial infarction. We examined whether elimination of impaired mitochondria was involved in p53 mediated infarct expansion.
Methods and Results: We performed left anterior descending artery permanent ligation in c57BL6 mice (WT) and p53 deficient mice (p53KO). Infarct size and the number of TUNEL positive cells in p53KO were significantly reduced (67.2% and 38.5% vs WT, respectively), in which mitochondrial DNA copy number and mitochondrial volume density were markedly decreased in p53KO (80.6% and 77.2% vs WT, respectively). GFP-LC3 transgenic × p53KO chimeric mice showed that GFP-labeled autophagosomes were markedly increased in ischemic area. Electron microscope images of ischemic myocardium demonstrated that the partition appeared inside mitochondria and mitophagy developed in p53KO. Furthermore, Parkin protein, a mediator of mitophagy, was consumed more in p53KO. These data indicated that mitochondrial dynamics and mitophagy were enhanced in p53KO compared with WT. We also found that myocardial ischemia rapidly phosphorylated p53 at ser-15 and consequently induced TIGAR (TP53-induced glycolysis and apoptosis regulator) in WT. Although cardiac protein level of Bnip3, a key interactor in mitophagy, was similar between WT and p53KO, Bnip3 in WT was inactivated by reduced reactive oxygen species (ROS) signal through TIGAR expression. Blocking autophagy by Chloroquine in p53KO decreased mitophagy and stimulated cytochrome C release into cytoplasm, which negated infarct size reduction.
Conclusion: Our present study demonstrates that p53-TIGAR mediated decrease in ROS generation reduces mitophagy via inactivation of Bnip3, resulting in the expansion of infarcted myocardium. Activation of mitophagy by suppressing p53 could be a novel therapeutic approach to myocardial infarction.
- © 2010 by American Heart Association, Inc.