| Endothelial PAS domain protein 1 (EPAS1) induces adrenomedullin gene expression in cardiac myocytes: role of EPAS1 in an inflammatory response in cardiac myocytes. | |
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MedLine Citation:
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PMID: 12099714 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Endothelial PAS domain protein 1 (EPAS1) has been identified as a member of the basic helix-loop-helix (bHLH)-PAS protein family, and plays a critical role in the regulation of hypoxia inducible genes. It remains unknown whether physiological stimuli other than hypoxia modulate EPAS1 expression. This study examined the inducible expression of EPAS1 by various cytokines and growth factors, and determined the target gene for EPAS1 in cardiac myocytes. In cultured cardiac myocytes, interleukin-1beta (IL-1beta) but not tumor necrosis factor alpha markedly increased the EPAS1 mRNA and protein levels in a time- and dose-dependent manner, whereas hypoxia increases the expression of EPAS1 protein but not its mRNA. Such an induction of EPAS1 by IL-1beta was efficiently inhibited by the pretreatment of the cells with Src kinase inhibitors, such as herbimycin A and PP1. The expression of adrenomedullin (AM) mRNA, which is also upregulated by IL-1beta, was dramatically increased in cardiac myocytes transduced with adenovirus expressing EPAS1. Transient transfection assays using the site-specific mutation of the AM promoter showed that EPAS1 overexpression increases the transcriptional activity through a sequence similar to the consensus HRE (hypoxia responsive element). These results suggest that IL-1beta induces the EPAS1 at the transcriptional level, which in turn activates the AM gene. Since IL-1beta has been implicated in the pathogenesis of heart failure and AM can ameliorate the cardiac function, our results suggest that EPAS1 plays a role in the adaptation of the cardiac myocytes during heart failure as well as in the regulation of gene expression by hypoxia. |
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Authors:
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Toru Tanaka; Hideo Akiyama; Hiroyoshi Kanai; Mahito Sato; Shinichi Takeda; Kenichi Sekiguchi; Tomoyuki Yokoyama; Masahiko Kurabayashi |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Journal of molecular and cellular cardiology Volume: 34 ISSN: 0022-2828 ISO Abbreviation: J. Mol. Cell. Cardiol. Publication Date: 2002 Jul |
Date Detail:
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Created Date: 2002-07-08 Completed Date: 2003-02-12 Revised Date: 2009-11-19 |
Medline Journal Info:
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Nlm Unique ID: 0262322 Medline TA: J Mol Cell Cardiol Country: England |
Other Details:
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Languages: eng Pagination: 739-48 Citation Subset: IM |
Copyright Information:
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Copyright 2002 Elsevier Science Ltd. All rights reserved. |
Affiliation:
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Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-15, Showa-machi, Maebashi, Gunma, 371-8511, Japan. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adrenomedullin Animals Basic Helix-Loop-Helix Transcription Factors Gene Expression Regulation Gene Transfer Techniques Heart Failure / metabolism Inflammation / metabolism Interleukin-1 / metabolism Myocytes, Cardiac / metabolism* Peptides / genetics, metabolism* Promoter Regions, Genetic RNA, Messenger / metabolism Rats Rats, Wistar Trans-Activators / metabolism* Up-Regulation src-Family Kinases / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Basic Helix-Loop-Helix Transcription Factors; 0/Interleukin-1; 0/Peptides; 0/RNA, Messenger; 0/Trans-Activators; 0/endothelial PAS domain-containing protein 1; 148498-78-6/Adrenomedullin; EC 2.7.10.2/src-Family Kinases |
| Comments/Corrections | |
Comment In:
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J Mol Cell Cardiol. 2002 Jul;34(7):703-7
[PMID:
12099709
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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