Abstract 10539: p53-Tigar Axis Attenuates Mitophagy Tt Exacerbate Cardiac Damage After Ischemia
Background: Inhibition of tumor suppressor p53 is cardioprotective against ischemic injury and resistant to subsequent cardiac remodeling. We investigated p53-mediated expansion of ischemic damage with the focus on mitochondrial integrity in association with autophagy and apoptosis.
Methods and Results: p53-/- mice exhibited more resistance to ischemic injury and less cardiac remodeling compared with wild-type mice (WT) without affecting cardiac tissue ATP content. In ischemic lesions, abnormal mitochondria and damaged mitochondrial DNA were accumulated less in p53-/- mice (56% and 70% decreases vs WT mice), while autophagic vacuoles containing mitochondria were increased as much as 5 fold in p53-/- mice. Real-time PCR analysis of molecules known as autophagic mediators acting downstream of p53 revealed that TIGAR (TP53-induced glycolysis and apoptosis regulator) was exclusively up-regulated in ischemic myocardium. Ischemic stress caused p53-dependent TIGAR expression and subsequent inactivation of Bnip3, leading to attenuation of mitophagy and myocyte survival. TIGAR-/- mice exhibited accelerated Bnip3 activation (237% increase), less accumulation of damaged mitochondrial DNA (72% decrease) and resistance to ischemia, consistent with p53-/- phenotype. In p53-/- and TIGAR-/- ischemic myocardium, ROS production was elevated and followed by Bnip3 activation which makes homodimer formation and acts as an initiator of mitophagy. Furthermore, the activation of Bnip3 and mitophagy due to p53/TIGAR inhibition was reversed with antioxidant N-acetyl-cysteine, indicating that this adaptive response requires ROS signal. Inhibiting mitophagy by chloroquine in p53-/- or TIGAR-/- mice exaggerated accumulation of damaged mitochondria and cytochrome c release from mitochondria to the WT level, and attenuated cardioprotective action.
Conclusion: Our present study demonstrates that p53/TIGAR-mediated inhibition of myocyte mitophagy is attributed to impairment of mitochondrial integrity and subsequent apoptosis, the process of which is closely involved in p53-mediated regulation of remodeling after myocardial ischemia.
- © 2011 by American Heart Association, Inc.