Epoxyeicosatrienoic Acids and/or Their Metabolites Promote Hypoxic Response of Cells
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概要
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Epoxyeicosatrienoic acids (EETs), including 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET, are produced by cytochrome P450 (P450) such as CYP2C8 and 2C9; and they are hydrolyzed to dihydroxyeicosatrienoic acids (DHETs) by epoxide hydrolase. 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 EETs. We focused on a new biological function of EETs and DHETs, which induce vascular endothelial growth factor (VEGF) and erythropoietin (EPO) under hypoxia. Human hepatoma cells, Hep3B, and human umbilical artery endothelial cells (HUAEC) were used in this study. An inhibitor of phospholipase A2, methyl arachidonyl fluorophosphonate (MAFP), and inhibitors of P450s inhibited the VEGF and EPO induction of HUAEC and Hep3B, respectively, under hypoxia. Overexpression of CYP2C8 in Hep3B induced EPO and VEGF under hypoxia. Sulfaphenazole, an inhibitor of CYP2C8/2C9 suppressed luciferase promoter activity with the hypoxia response element (HRE) of VEGF in HUAEC. Exogenous 11,12-EET and 14,15-DHET induced reporter activity in HUAEC and Hep3B cells concomitant with increased levels of hypoxia-inducible factor-1α (HIF-1α), which is a key factor in the hypoxia response, but 11,12-DHET and 14,15-EET did not. These results suggested that EETs and DHETs play an important role in the hypoxia response of cells.
- 2008-09-20
著者
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IMAOKA Susumu
Nanobiotechnology Research Center and Department of Bioscience, School of Science and Technology, Kw
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FUNAE Yoshihiko
Department of Chemical Biology, Osaka City University Graduate School of Medicine
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Osada Oka
Department Of Pathological Biochemistry Kyoto Pharmaceutical University
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Funae Yoshihiko
Department Of Chemical Biology Osaka City University Graduate School Of Medicine
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Funae Yoshihiko
Department Of Chemical Biology Osaka City University Medical School
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Oguro Ami
Nanobiotechnology Research Center and Department of Bioscience, School of Science and Technology, Kw
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Suzuki Sachiko
Nanobiotechnology Research Center and Department of Bioscience, School of Science and Technology, Kw
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Imaoka Susumu
Nanobiotechnology Res. Center And Dep. Of Bioscience School Of Sci. And Technol. Kwansei Gakuin Univ
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Oguro Ami
Nanobiotechnology Research Center And Department Of Bioscience School Of Science And Technology Kwan
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Osada Oka
Department Of Bacteriology Osaka City University Graduate School Of Medicine
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Suzuki Sachiko
Graduate School Of Pharmaceutical Sciences The University Of Tokyo
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Osada-Oka Mayuko
Department of Pathological Biochemistry, Kyoto Pharmaceutical University
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