期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 280, 期 39, 页码 33157-33164出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M504055200
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资金
- NCRR NIH HHS [RR13799] Funding Source: Medline
- NHLBI NIH HHS [HL62984, HL70860, HL72845, HL76684] Funding Source: Medline
- NIAAA NIH HHS [AA00279, AA09731] Funding Source: Medline
- NIGMS NIH HHS [GM31278] Funding Source: Medline
- NINDS NIH HHS [NS24621] Funding Source: Medline
20-Carboxyeicosatetraenoic acid (20-COOH-AA) is a bioactive metabolite of 20-hydroxyeicosatetraenoic acid (20-HETE), an eicosanoid that produces vasoconstriction in the cerebral circulation. We found that smooth muscle (MSMC) and endothelial (MEC) cultures obtained from mouse brain microvessels convert [H-3] 20-HETE to 20-COOH-AA, indicating that the cerebral vasculature can produce this metabolite. The [H-3] 20-COOH-AA accumulated primarily in the culture medium, together with additional radiolabeled metabolites identified as the chain-shortened dicarboxylic acids 18-COOH-18: 4, 18-COOH-18: 3, and 16-COOH-16: 3. N-Heptylformamide, a potent inhibitor of alcohol dehydrogenase (ADH), decreased the conversion of [H-3] 20-HETE to 20-COOH-AA by the MSMC and MEC and also by isolated mouse brain microvessels. Purified mouse and human ADH4, human ADH3, and horse liver ADH1 efficiently oxidized 20-HETE, and ADH4 and ADH3 were detected in MSMC and MEC by Western blotting. N-Heptylformamide inhibited the oxidation of 20-HETE by mouse and human ADH4 but not by ADH3. These results demonstrated that cerebral microvessels convert 20-HETE to 20-COOH-AA and that ADH catalyzes the reaction. Although ADH4 and ADH3 are expressed in MSMC and MEC, the inhibition produced by N-heptylformamide suggests that ADH4 is primarily responsible for 20-COOH-AA formation in the cerebral microvasculature.
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