RRC ID 27898
著者 Hoshino A, Matoba S, Iwai-Kanai E, Nakamura H, Kimata M, Nakaoka M, Katamura M, Okawa Y, Ariyoshi M, Mita Y, Ikeda K, Ueyama T, Okigaki M, Matsubara H.
タイトル p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia.
ジャーナル J Mol Cell Cardiol
Abstract Inhibition of tumor suppressor p53 is cardioprotective against ischemic injury and provides resistance to subsequent cardiac remodeling. We investigated p53-mediated expansion of ischemic damage with a focus on mitochondrial integrity in association with autophagy and apoptosis. p53(-/-) heart showed that autophagic flux was promoted under ischemia without a change in cardiac tissue ATP content. Electron micrographs revealed that ischemic border zone in p53(-/-) mice had 5-fold greater numbers of autophagic vacuoles containing mitochondria, indicating the occurrence of mitophagy, with an apparent reduction of abnormal mitochondria compared with those in WT mice. Analysis of autophagic mediators acting downstream of p53 revealed that TIGAR (TP53-induced glycolysis and apoptosis regulator) was exclusively up-regulated in ischemic myocardium. TIGAR(-/-) mice exhibited the promotion of mitophagy followed by decrease of abnormal mitochondria and resistance to ischemic injury, consistent with the phenotype of p53(-/-) mice. In p53(-/-) and TIGAR(-/-) ischemic myocardium, ROS production was elevated and followed by Bnip3 activation which is an initiator of mitophagy. Furthermore, the activation of Bnip3 and mitophagy due to p53/TIGAR inhibition were reversed with antioxidant N-acetyl-cysteine, indicating that this adaptive response requires ROS signal. Inhibition of mitophagy using chloroquine in p53(-/-) or TIGAR(-/-) mice exacerbated accumulation of damaged mitochondria to the level of wild-type mice and attenuated cardioprotective action. These findings indicate that p53/TIGAR-mediated inhibition of myocyte mitophagy is responsible for impairment of mitochondrial integrity and subsequent apoptosis, the process of which is closely involved in p53-mediated ventricular remodeling after myocardial infarction.
巻・号 52(1)
ページ 175-84
公開日 2012-1-1
DOI 10.1016/j.yjmcc.2011.10.008
PII S0022-2828(11)00435-4
PMID 22044588
MeSH Animals Apoptosis / genetics Apoptosis Regulatory Proteins Autophagy / genetics Gene Expression Regulation Membrane Proteins / genetics Membrane Proteins / metabolism Mice Mice, Inbred C57BL Mice, Knockout Mitochondria, Heart / metabolism Mitochondria, Heart / pathology Mitochondrial Proteins / genetics Mitochondrial Proteins / metabolism Myocardial Infarction / genetics Myocardial Infarction / metabolism Myocardial Ischemia / genetics Myocardial Ischemia / metabolism* Oxidative Stress Phosphoric Monoester Hydrolases Proteins / genetics Proteins / metabolism* Reactive Oxygen Species / metabolism Tumor Suppressor Protein p53 / genetics Tumor Suppressor Protein p53 / metabolism* Ventricular Remodeling / genetics
IF 4.133
引用数 99
WOS 分野 CARDIAC & CARDIOVASCULAR SYSTEMS CELL BIOLOGY
リソース情報
実験動物マウス RBRC00806