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Originally published In Press as doi:10.1074/jbc.M011761200 on February 7, 2001

J. Biol. Chem., Vol. 276, Issue 18, 14867-14874, May 4, 2001
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Pathways of Epoxyeicosatrienoic Acid Metabolism in Endothelial Cells
IMPLICATIONS FOR THE VASCULAR EFFECTS OF SOLUBLE EPOXIDE HYDROLASE INHIBITION*

Xiang FangDagger , Terry L. KaduceDagger , Neal L. Weintraub§, Shawn HarmonDagger , Lynn M. Teesch, Christophe Morisseau||, David A. Thompson||, Bruce D. Hammock||, and Arthur A. SpectorDagger §Dagger Dagger

From the Departments of Dagger  Biochemistry, § Internal Medicine, and  Molecular Analysis Facility, College of Medicine, University of Iowa, Iowa City, Iowa 52242 and the || Department of Entomology and Cancer Research Center, University of California, Davis, California 95616

Epoxyeicosatrienoic acids (EETs) are products of cytochrome P-450 epoxygenase that possess important vasodilating and anti-inflammatory properties. EETs are converted to the corresponding dihydroxyeicosatrienoic acid (DHET) by soluble epoxide hydrolase (sEH) in mammalian tissues, and inhibition of sEH has been proposed as a novel approach for the treatment of hypertension. We observed that sEH is present in porcine coronary endothelial cells (PCEC), and we found that low concentrations of N,N'-dicyclohexylurea (DCU), a selective sEH inhibitor, have profound effects on EET metabolism in PCEC cultures. Treatment with 3 µM DCU reduced cellular conversion of 14,15-EET to 14,15-DHET by 3-fold after 4 h of incubation, with a concomitant increase in the formation of the novel beta -oxidation products 10,11-epoxy-16:2 and 8,9-epoxy-14:1. DCU also markedly enhanced the incorporation of 14,15-EET and its metabolites into PCEC lipids. The most abundant product in DCU-treated cells was 16,17-epoxy-22:3, the elongation product of 14,15-EET. Another novel metabolite, 14,15-epoxy-20:2, was present in DCU-treated cells. DCU also caused a 4-fold increase in release of 14,15-EET when the cells were stimulated with a calcium ionophore. Furthermore, DCU decreased the conversion of [3H]11,12-EET to 11,12-DHET, increased 11,12-EET retention in PCEC lipids, and produced an accumulation of the partial beta -oxidation product 7,8-epoxy-16:2 in the medium. These findings suggest that in addition to being metabolized by sEH, EETs are substrates for beta -oxidation and chain elongation in endothelial cells and that there is considerable interaction among the three pathways. The modulation of EET metabolism by DCU provides novel insight into the mechanisms by which pharmacological or molecular inhibition of sEH effectively treats hypertension.

* This study was supported by National Institutes of Health Program Project Grants HL49264 and HL62984 (to A. A. S. and N. L. W.), by an American Heart Association Heartland Affiliate Beginning Grant-in-aid 0060413Z (to X. F.), by an American Heart Association Clinician-Scientist Award 96004540 (to N. L. W.), by NIEHS Grant R01 ES02710, the NIEHS Superfund Basic Research Program P42 ES04699, and NIEHS Center P30 ES05707 (to B. D. H.) from the National Institutes of Health, and by National Institutes of Health Training Grant HL07013 (to D. A. T.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger Dagger To whom correspondence should be addressed: Dept. of Biochemistry, 4-403 BSB, University of Iowa, Iowa City, IA 52242. Tel.: 319-335-7913; Fax: 319-335-9570; E-mail: arthur-spector@uiowa.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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