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 |