Atrial natriuretic peptide (ANP) is a cardiac peptide, the transcription of which is up-regulated in the ischaemic ventricle. However, the molecular mechanism of ANP induction is unclear. This study demonstrated that ANP mRNA expression in rat ventricular myocardium is induced in an early phase of ischaemia, preceded by hypoxia-inducible factor-1 (HIF-1) α expression. The ANP gene was also induced by hypoxia or HIF-1 inducers such as CoCl2 and desferrioxamine in H9c2 and neonatal cardiomyocytes. The 2307bp 5′-flanking region of the rat ANP gene was cloned and fused to the luciferase gene. Evidence of the promoter activity was only apparent in the myocytes and was induced by hypoxia and HIF-1 inducers. The overexpression of HIF-1α markedly enhanced ANP promoter activity, and a dominant-negative isoform completely suppressed it. We demonstrated that the promoter regions are essential for hypoxic ANP induction. One promoter region, containing the HIF-1-binding sequence, is regulated directly by HIF-1. The other region is also activated by HIF-1 despite having no HIF-1-binding sequence. These results suggest that HIF-1 enhances the transactivation of the ANP gene in hypoxic myocytes, implying that stimulation of the ANP promoter by HIF-1 may in fact be responsible for the induction of the ANP gene in ischaemic ventricular myocardium.
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February 2003
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Research Article|
February 15 2003
Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1
Yang-Sook CHUN;
Yang-Sook CHUN
∗Human Genome Research Institute and Cancer Research Institute, BK21 Human Life Sciences, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea
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Ju-Yeon HYUN;
Ju-Yeon HYUN
†Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea
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Yong-Geun KWAK;
Yong-Geun KWAK
‡Department of Pharmacology, Chonbuk National University College of Medicine, Chonju, South Korea,
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In-San KIM;
In-San KIM
§Department of Biochemistry, Kyungpook National University, College of Medicine, Taegu, South Korea
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Chan-Hyung KIM;
Chan-Hyung KIM
†Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea
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Eunjoo CHOI;
Eunjoo CHOI
†Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea
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Myung-Suk KIM;
Myung-Suk KIM
†Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea
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Jong-Wan PARK
Jong-Wan PARK
1
†Department of Pharmacology, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, South Korea
1To whom correspondence should be addressed (e-mail parkjw@plaza.snu.ac.kr).
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Publisher: Portland Press Ltd
Received:
July 10 2002
Revision Received:
October 30 2002
Accepted:
November 04 2002
Accepted Manuscript online:
November 04 2002
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2003
2003
Biochem J (2003) 370 (1): 149–157.
Article history
Received:
July 10 2002
Revision Received:
October 30 2002
Accepted:
November 04 2002
Accepted Manuscript online:
November 04 2002
Citation
Yang-Sook CHUN, Ju-Yeon HYUN, Yong-Geun KWAK, In-San KIM, Chan-Hyung KIM, Eunjoo CHOI, Myung-Suk KIM, Jong-Wan PARK; Hypoxic activation of the atrial natriuretic peptide gene promoter through direct and indirect actions of hypoxia-inducible factor-1. Biochem J 15 February 2003; 370 (1): 149–157. doi: https://doi.org/10.1042/bj20021087
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