title: Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury.
abstract: BACKGROUND
  The number of patients with coronary heart disease, including myocardial infarction, is increasing and novel therapeutic strategy is awaited. Tumor suppressor protein p53 accumulates in the myocardium after myocardial infarction, causes apoptosis of cardiomyocytes, and plays an important role in the progression into heart failure.
  
  
  OBJECTIVE
  We investigated the molecular mechanisms of p53 accumulation in the heart after myocardial infarction and tested whether anti-p53 approach would be effective against myocardial infarction.
  
  
  RESULTS
  Through expression screening, we found that CHIP (carboxyl terminus of Hsp70-interacting protein) is an endogenous p53 antagonist in the heart. CHIP suppressed p53 level by ubiquitinating and inducing proteasomal degradation. CHIP transcription was downregulated after hypoxic stress and restoration of CHIP protein level prevented p53 accumulation after hypoxic stress. CHIP overexpression in vivo prevented p53 accumulation and cardiomyocyte apoptosis after myocardial infarction. Promotion of CHIP function by heat shock protein (Hsp)90 inhibitor, 17-allylamino-17-demethoxy geldanamycin (17-AAG), also prevented p53 accumulation and cardiomyocyte apoptosis both in vitro and in vivo. CHIP-mediated p53 degradation was at least one of the cardioprotective effects of 17-AAG.
  
  
  CONCLUSIONS
  We found that downregulation of CHIP level by hypoxia was responsible for p53 accumulation in the heart after myocardial infarction. Decreasing the amount of p53 prevented myocardial apoptosis and ameliorated ventricular remodeling after myocardial infarction. We conclude that anti-p53 approach would be effective to treat myocardial infarction.
authors.affiliation: Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.forename: Sho
authors.initials: S
authors.lastname: Okada
authors.forename: Tohru
authors.initials: T
authors.lastname: Minamino
authors.forename: Koji
authors.initials: K
authors.lastname: Iwanaga
authors.forename: Mei-Lan
authors.initials: ML
authors.lastname: Liu
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Sumida
authors.forename: Seitaro
authors.initials: S
authors.lastname: Nomura
authors.forename: Naruhiko
authors.initials: N
authors.lastname: Sahara
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Mizoroki
authors.forename: Akihiko
authors.initials: A
authors.lastname: Takashima
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.forename: Toshio
authors.initials: T
authors.lastname: Nagai
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001483:Base Sequence; D016227:Benzoquinones / Q000494:pharmacology; D019556:COS Cells; D015687:Cell Hypoxia; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D034622:RNA Interference; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination; D020257:Ventricular Remodeling
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; C497443:Hif1a protein, mouse; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047029:Lactams, Macrocyclic; D016159:Tumor Suppressor Protein p53; C112765:tanespimycin; C467728:STUB1 protein, human; C492951:Stub1 protein, mouse; C540442:Stub1 protein, rat; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex