| Insulin-like growth factor-1 induces Mdm2 and down-regulates p53, attenuating the myocyte renin-angiotensin system and stretch-mediated apoptosis. | |
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MedLine Citation:
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PMID: 10027414 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Insulin-like growth factor (IGF)-1 inhibits apoptosis, but its mechanism is unknown. Myocyte stretching activates p53 and p53-dependent genes, leading to the formation of angiotensin II (Ang II) and apoptosis. Therefore, this in vitro system was used to determine whether IGF-1 interfered with p53 function and the local renin-angiotensin system (RAS), decreasing stretch-induced cell death. A single dose of 200 ng/ml IGF-1 at the time of stretching decreased myocyte apoptosis 43% and 61% at 6 and 20 hours. Ang II concentration was reduced 52% at 20 hours. Additionally, p53 DNA binding to angiotensinogen (Aogen), AT1 receptor, and Bax was markedly down-regulated by IGF-1 via the induction of Mdm2 and the formation of Mdm2-p53 complexes. Concurrently, the quantity of p53, Aogen, renin, AT1 receptor, and Bax was reduced in stretched myocytes exposed to IGF-1. Conversely, Bcl-2 and the Bcl-2-to-Bax protein ratio increased. The effects of IGF-1 on cell death, Ang II synthesis, and Bax protein were the consequence of Mdm2-induced down-regulation of p53 function. In conclusion, the anti-apoptotic impact of IGF-1 on stretched myocytes was mediated by its capacity to depress p53 transcriptional activity, which limited Ang II formation and attenuated the susceptibility of myocytes to trigger their endogenous cell death pathway. |
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Authors:
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A Leri; Y Liu; P P Claudio; J Kajstura; X Wang; S Wang; P Kang; A Malhotra; P Anversa |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S. |
Journal Detail:
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Title: The American journal of pathology Volume: 154 ISSN: 0002-9440 ISO Abbreviation: Am. J. Pathol. Publication Date: 1999 Feb |
Date Detail:
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Created Date: 1999-03-04 Completed Date: 1999-03-04 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370502 Medline TA: Am J Pathol Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 567-80 Citation Subset: AIM; IM; S |
Affiliation:
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Department of Medicine, New York Medical College, Valhalla 10595, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Angiotensin II
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metabolism Angiotensinogen / metabolism Animals Apoptosis* Cells, Cultured DNA Primers / chemistry DNA-Binding Proteins / metabolism Down-Regulation Heart Ventricles / cytology, drug effects, metabolism In Situ Nick-End Labeling Insulin-Like Growth Factor I / pharmacology* Myocardium / cytology* Nuclear Proteins* Proto-Oncogene Proteins / biosynthesis* Proto-Oncogene Proteins c-mdm2 Rats Rats, Sprague-Dawley Renin-Angiotensin System / drug effects*, physiology Stress, Mechanical Tumor Suppressor Protein p53 / genetics, metabolism* |
| Grant Support | |
ID/Acronym/Agency:
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AG-15756/AG/NIA NIH HHS; HL-38132/HL/NHLBI NIH HHS; HL-43023/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/DNA Primers; 0/DNA-Binding Proteins; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins; 0/Tumor Suppressor Protein p53; 11002-13-4/Angiotensinogen; 11128-99-7/Angiotensin II; 67763-96-6/Insulin-Like Growth Factor I; EC 6.3.2.19/Mdm2 protein, rat; EC 6.3.2.19/Proto-Oncogene Proteins c-mdm2 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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