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

doi:10.1074/jbc.M504055200

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ω-Oxidation of 20-Hydroxyeicosatetraenoic Acid (20-HETE) in Cerebral Microvascular Smooth Muscle and Endothelium by Alcohol Dehydrogenase 4

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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, …

The Journal of biological chemistry, Vol.280(39), pp.33157-33164

09/30/2005

DOI: 10.1074/jbc.M504055200

PMID: 16081420

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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.

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Title: Subtitle: ω-Oxidation of 20-Hydroxyeicosatetraenoic Acid (20-HETE) in Cerebral Microvascular Smooth Muscle and Endothelium by Alcohol Dehydrogenase 4
Creators: Xixuan H Collins - University of Iowa
Shawn D Harmon - University of Iowa
Terry L Kaduce - University of Iowa
Kristine B Berst - University of Iowa
Xiang Fang - University of Iowa
Steven A Moore - University of Iowa
T. Verugopal Raju - Southwestern Medical Center
John R Falck - Southwestern Medical Center
Neal L Weintraub - University of Iowa
Gregg Duester - Sanford Burnham Prebys Medical Discovery Institute
Bryce V Plapp - University of Iowa
Arthur A Spector - University of Iowa
Resource Type: Journal article
Publication Details: The Journal of biological chemistry, Vol.280(39), pp.33157-33164
DOI: 10.1074/jbc.M504055200
PMID: 16081420
NLM abbreviation: J Biol Chem
ISSN: 0021-9258
eISSN: 1083-351X
Publisher: Elsevier Inc
Alternative title: Omega-oxidation of 20-hydroxyeicosatetraenoic acid (20-HETE) in cerebral microvascular smooth muscle and endothelium by alcohol dehydrogenase 4
Language: English
Date published: 09/30/2005
Academic Unit: Pathology; Biochemistry and Molecular Biology; Internal Medicine
Record Identifier: 9984186501402771

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