Promotion of CHIP-Mediated p53 Degradation Protects the Heart From Ischemic Injury

Autor: Koji Iwanaga, Toshio Nagai, Hiroshi Akazawa, Issei Komuro, Sho Okada, Tohru Minamino, Tomokazu Sumida, Seitaro Nomura, Ichiro Shiojima, Naruhiko Sahara, Atsuhiko T. Naito, Akihiko Takashima, Tatsuya Mizoroki, Mei-Lan Liu
Rok vydání: 2010
Předmět:
Male
Physiology
Myocardial Infarction
Apoptosis
Endogeny
law.invention
Mice
Transcription (biology)
law
Chlorocebus aethiops
Benzoquinones
Myocytes
Cardiac
Myocardial infarction
Promoter Regions
Genetic
Mice
Knockout
Ventricular Remodeling
Cell Hypoxia
COS Cells
Cardiology
RNA Interference
Cardiology and Cardiovascular Medicine
Transcriptional Activation
Proteasome Endopeptidase Complex
medicine.medical_specialty
Lactams
Macrocyclic
Ubiquitin-Protein Ligases
Molecular Sequence Data
In vivo
Internal medicine
medicine
Animals
Humans
HSP90 Heat-Shock Proteins
Rats
Wistar
Base Sequence
business.industry
Ubiquitination
Antagonist
Genetic Therapy
Hypoxia-Inducible Factor 1
alpha Subunit
medicine.disease
Rats
Mice
Inbred C57BL
Disease Models
Animal
Animals
Newborn
Heart failure
Mutation
Cancer research
Suppressor
Tumor Suppressor Protein p53
business
Protein Processing
Post-Translational
Zdroj: Circulation Research. 106:1692-1702
ISSN: 1524-4571
0009-7330
Popis: Rationale : 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. Objectives : 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. Methods and 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.
Databáze: OpenAIRE
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