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2005 Fiscal Year Final Research Report Summary

Biological role of EET in induction of vascular endotberial growth factor underr hypoxia

Research Project

Project/Area Number 16590129
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Medical pharmacy
Research InstitutionKwansei Gakuin University

Principal Investigator

IMAOKA Susumu  Kwansei Gakuin University, School of Science and Technology, Professor, 理工学部, 教授 (60145795)

Project Period (FY) 2004 – 2005
Keywordshypoxia / VEGF / EET / HUAEC / cytochrome P450
Research Abstract

Cytochrome P450 (P450) catalyze the NADPH-dependent oxidation of arachidonic acid to several unique eicosanoids such as epoxyeicosatrienoic acid (EET) which has four isomers, 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET. A particular interest in the epoxygenase reaction has developed because of the potent biological activities (modulation of vascular tone and anti-inflammatory activity etc.) attributed to the EETs. I focused on a new biological function of EETs which induce vascular endotherial growth factor (VEGF) under hypoxia. In this study, human hepatoma cell, Hep3B and human umbilical artery endotherial cell (HUAEC) were used under normoxic and hypoxic conditions. An inhibitor for phospholipase A2 which supplies arachidonic acid from plasma membrane, MAFP, inhibited the VEGF induction in HUAEC under hypoxia. NADPH-P450 reductase (NPR) supplies electrons to P450 and is necessary for P450 to oxidize arachidonic acid. An inhibitor for NPR, DPIC, inhibited the VEGF induction. These results suggest that arachidonic acid and P450 are important for the VEGF induction in HUAEC under hypoxia. The same effects on Hep3B cells were also observed. In Hep3B cells, inhibitors for P450s, sulfaphenazol (an inhibitor for CYP2C8 and CYP2C9) and ketoconazole (an inhibitor for CYP3A) inhibited hypoxia response (erythropoietin induction) efficiently. Addition of 11,12-EET or 14,15-EET induced VEGF in HUAEC under hypoxia but hydration products, 11,12-DHETE and 14,15-DHETE did not induce VEGF. Hypoxia-inducible factor (HIF-1) is necessary for induction of VEGF under hypoxia. 11,12-EET and 14,15-EET did not change the levels of HIF-1. In conclusion, EETs produced by P450s play an important role in hypoxic response of cells. EETs induced VEGF independent on HIF-1 which is an important factor of hypoxic response.

  • Research Products

    (21 results)

All 2006 2005 2004

All Journal Article (21 results)

  • [Journal Article] Bisphenol A binds to Protein Disulfide Isomerase and inhibits its enzymatic and hormone-binding activities.2006

    • Author(s)
      Hioi, T. et al.
    • Journal Title

      Endocrinolpgy 147(6)

      Pages: 2773-2780

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Purification of NADPH-P450 reductanse (NPR) from Xenopus laevis and the developmental change in NPR exression.2006

    • Author(s)
      Mori, T. et al.
    • Journal Title

      Life Sci. 79(3)

      Pages: 247-251

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Bisphenol A binds to Protein Disulfide Isomerase and inhibits its enzymatic and hormone-binding activities.2006

    • Author(s)
      Hiroi, T. et al.
    • Journal Title

      Endocrinology. 147(6)

      Pages: 2773-2780

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Purification of NADPH-P450 reductase (NPR) from Xenopus laevis and the developmental change in NPR expression.2006

    • Author(s)
      Mori, T. et al.
    • Journal Title

      Life Sci. 79(3)

      Pages: 247-251

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] A new epitope of CYP2D6 recognized by liver kidney microsomal autoantibody from japanese patients with autoimmune hepatitis.2005

    • Author(s)
      Imaoka, S. et al.
    • Journal Title

      Biol. Pharm. Bull, 28(12)

      Pages: 2240-2243

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cytochrome P450 2E polymorphism in feline liver.2005

    • Author(s)
      Tanaka, N. et al.
    • Journal Title

      Biochim.Biophys.Acta 1726(2)

      Pages: 194-205

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Inhibitory effects of environmental chemicals on protein disulfide isomerase in vitro.2005

    • Author(s)
      Okada, T. et al.
    • Journal Title

      Osaka City Med. J. 51(2)

      Pages: 51-63

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Localization of rat cytochrome P450 in various tissues and comparison of arachidonic acid metabolism of rat P450 with that human P450 orthologs.2005

    • Author(s)
      Imaoka, S. et al.
    • Journal Title

      Drug Metab. and Phamacokinet. 20(6)

      Pages: 478-484

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] A new epitope of CYP2D6 recognized by liver kidney microsomal autoantibody from japanese patients with autoimmune hepatitis.2005

    • Author(s)
      Imaoka, S. et al.
    • Journal Title

      Biol.Pharm.Bull. 28(12)

      Pages: 2240-2243

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Inhibitory effects of environmental chemicals on protein disulfide isomerase in vitro.2005

    • Author(s)
      Okada, K. et al.
    • Journal Title

      Osaka City Med.J. 51(2)

      Pages: 51-63

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Localization of rat cytochrome P450 in various tissues and comparison of arachidonic acid metabolism of rat P450 with that of human P450 orthologs.2005

    • Author(s)
      Imaoka, S. et al.
    • Journal Title

      Drug Metab.and Phamacokinet. 20(6)

      Pages: 478-484

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation.2004

    • Author(s)
      Imaoka, S, et al.
    • Journal Title

      Cancer Lett. 203(2)

      Pages: 117-125

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brein.2004

    • Author(s)
      Kishimoto, W. et al.
    • Journal Title

      Endocrinology 145(2)

      Pages: 699-705

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Bisphenol A,an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1 (HIH-1alpha)2004

    • Author(s)
      Kubo, T. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 318(4)

      Pages: 1006-1011

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] CYP3A inductuion aggravates endotoxemic liver injury via reactive oxygen species in male rats.2004

    • Author(s)
      Minamiyama, Y. et al.
    • Journal Title

      Free Radic.Biol.Med. 37(5)

      Pages: 703-712

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Apigenin suppresses the expression of VEGF,an important factor for angiogenesis,in endothelial cells via degradation of HIH-1alpha protein.2004

    • Author(s)
      Osada, M. et al.
    • Journal Title

      FEBS Lett. 575(1-3)

      Pages: 59-63

    • Description
      「研究成果報告書概要(和文)」より
  • [Journal Article] Role of phenobarbital-inducible cytochrome P450s as a source of active oxygen species in DNA-oxidation.2004

    • Author(s)
      Imaoka, S. et al.
    • Journal Title

      Cancer Lett. 203(2)

      Pages: 117-125

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Cytochrome P450 2D catalyze steroid 21-hydroxylation in the brain.2004

    • Author(s)
      Kishimoto, W. et al.
    • Journal Title

      Endocrinology 145(2)

      Pages: 699-705

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Bisphenol A, an environmental endocrine-disrupting chemical, inhibits hypoxic response via degradation of hypoxia-inducible factor 1 (HIF-1alpha).2004

    • Author(s)
      Kubo, T. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 318(4)

      Pages: 1006-1011

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] CYP3A induction aggravates endotoxemic liver injury via reactive oxygen species in male rats.2004

    • Author(s)
      Minamiyama, Y. et al.
    • Journal Title

      Free Radic.Biol.Med. 37(5)

      Pages: 703-712

    • Description
      「研究成果報告書概要(欧文)」より
  • [Journal Article] Apigenin suppresses the expression of VEGF, an important factor for angiogenesis, in endothelial cells via degradation of HIF-1alpha protein.2004

    • Author(s)
      Osada, M. et al.
    • Journal Title

      FEBS Lett. 575(1-3)

      Pages: 59-63

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 2007-12-13  

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