HIF-1 (hypoxia-inducible factor 1) is a master regulator of cellular adaptive responses to hypoxia. The expression and transcriptional activity of the HIF-1α subunit is stringently controlled by intracellular oxygen tension through the action of prolyl and asparaginyl hydroxylases. In the present study we demonstrate that PG (n-propyl gallate) activates HIF-1 and expression of its downstream target genes under normoxic conditions in cultured cells and in mice. The stability and transcriptional activity of HIF-1α are increased by PG. PG treatment inhibits the interaction between HIF-1α and VHL (von Hippel–Lindau protein) and promotes the interaction between HIF-1α and p300, indicating that PG inhibits the activity of both prolyl and asparaginyl HIF-1α hydroxylases. We conclude that PG activates HIF-1 and enhances the resultant gene expression by directly affecting the intracellular oxygen sensing system in vitro and in vivo and that PG represents a lead compound for the development of a non-toxic activator of HIF-1.
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Research Article|
March 13 2008
n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems
Motohide Kimura;
Motohide Kimura
1
*Department of Surgery, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan
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Satoshi Takabuchi;
Satoshi Takabuchi
1
†Department of Anesthesia, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
‡Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan
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Tomoharu Tanaka;
Tomoharu Tanaka
‡Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan
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Miyahiko Murata;
Miyahiko Murata
§Department of Integrative Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Kenichiro Nishi;
Kenichiro Nishi
†Department of Anesthesia, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
∥Department of Anesthesiology, Kansai Medical University, Moriguchi, Osaka 570-8506, Japan
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Seiko Oda;
Seiko Oda
†Department of Anesthesia, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
‡Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan
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Tomoyuki Oda;
Tomoyuki Oda
¶Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto University, Kyoto 606-8501, Japan
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Michiyuki Kanai;
Michiyuki Kanai
*Department of Surgery, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan
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Kazuhiko Fukuda;
Kazuhiko Fukuda
‡Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan
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Shinae Kizaka-Kondoh;
Shinae Kizaka-Kondoh
**Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Takehiko Adachi;
Takehiko Adachi
†Department of Anesthesia, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
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Arimichi Takabayashi;
Arimichi Takabayashi
*Department of Surgery, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka, 530-8480, Japan
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Gregg L. Semenza;
Gregg L. Semenza
††Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, 733 North Broadway, Baltimore, MD 21205, U.S.A.
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Kiichi Hirota
Kiichi Hirota
2
†Department of Anesthesia, The Tazuke Kofukai Medical Research Institute, Kitano Hospital, 2-4-20 Ohgimachi, Kita-ku, Osaka 530-8480, Japan
‡Department of Anesthesia, Kyoto University Hospital, Kyoto 606-8507, Japan
2To whom correspondence should be addressed (email hif1@mac.com).
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Publisher: Portland Press Ltd
Received:
June 21 2007
Revision Received:
November 15 2007
Accepted:
November 30 2007
Accepted Manuscript online:
November 30 2007
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2008 Biochemical Society
2008
Biochem J (2008) 411 (1): 97–105.
Article history
Received:
June 21 2007
Revision Received:
November 15 2007
Accepted:
November 30 2007
Accepted Manuscript online:
November 30 2007
Citation
Motohide Kimura, Satoshi Takabuchi, Tomoharu Tanaka, Miyahiko Murata, Kenichiro Nishi, Seiko Oda, Tomoyuki Oda, Michiyuki Kanai, Kazuhiko Fukuda, Shinae Kizaka-Kondoh, Takehiko Adachi, Arimichi Takabayashi, Gregg L. Semenza, Kiichi Hirota; n-Propyl gallate activates hypoxia-inducible factor 1 by modulating intracellular oxygen-sensing systems. Biochem J 1 April 2008; 411 (1): 97–105. doi: https://doi.org/10.1042/BJ20070824
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