title: p53-TIGAR axis attenuates mitophagy to exacerbate cardiac damage after ischemia.
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.
authors: Department of Cardiovascular Medicine, Kyoto Prefectural University School of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.
authors: Atsushi
authors: A
authors: Hoshino
authors: Satoaki
authors: S
authors: Matoba
authors: Eri
authors: E
authors: Iwai-Kanai
authors: Hideo
authors: H
authors: Nakamura
authors: Masaki
authors: M
authors: Kimata
authors: Mikihiko
authors: M
authors: Nakaoka
authors: Maki
authors: M
authors: Katamura
authors: Yoshifumi
authors: Y
authors: Okawa
authors: Makoto
authors: M
authors: Ariyoshi
authors: Yuichiro
authors: Y
authors: Mita
authors: Koji
authors: K
authors: Ikeda
authors: Tomomi
authors: T
authors: Ueyama
authors: Mitsuhiko
authors: M
authors: Okigaki
authors: Hiroaki
authors: H
authors: Matsubara
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins; D001343:Autophagy / Q000235:genetics; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010744:Phosphoric Monoester Hydrolases; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D020257:Ventricular Remodeling / Q000235:genetics
chemical_list: D051017:Apoptosis Regulatory Proteins; C508686:BNip3 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D010744:Phosphoric Monoester Hydrolases; C554952:TIGAR protein, mouse