ω-oxidation of 20-hydroxyeicosatetraenoic acid (20-HETE) in cerebral microvascular smooth muscle and endothelium by alcohol dehydrogenase 4

Xixuan H. Collins, Shawn D. Harmon, Terry L. Kaduce, Kristine B. Berst, Xiang Fang, Steven A. Moore, T. Verugopal Raju, John R. Falck, Neal L. Weintraub, Gregg Duester, Bryce V. Plapp, Arthur A. Spector

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

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 [3H] 20-HETE to 20-COOH-AA, indicating that the cerebral vasculature can produce this metabolite. The [3H] 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 [3H]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.

Original languageEnglish (US)
Pages (from-to)33157-33164
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number39
DOIs
StatePublished - Sep 30 2005
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Collins, X. H., Harmon, S. D., Kaduce, T. L., Berst, K. B., Fang, X., Moore, S. A., Raju, T. V., Falck, J. R., Weintraub, N. L., Duester, G., Plapp, B. V., & Spector, A. A. (2005). ω-oxidation of 20-hydroxyeicosatetraenoic acid (20-HETE) in cerebral microvascular smooth muscle and endothelium by alcohol dehydrogenase 4. Journal of Biological Chemistry, 280(39), 33157-33164. https://doi.org/10.1074/jbc.M504055200