Pathways of epoxyeicosatrienoic acid metabolism in endothelial cells. Implications for the vascular effects of soluble epoxide hydrolase inhibition

Xiang Fang, Terry L. Kaduce, Neal Lee Weintraub, Shawn Harmon, Lynn M. Teesch, Christophe Morisseau, David A. Thompson, Bruce D. Hammock, Arthur A. Spector

Research output: Contribution to journalArticle

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Abstract

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 β-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 [ 3 H]11,12-EET to 11,12-DHET, increased 11,12-EET retention in PCEC lipids, and produced an accumulation of the partial β-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 β-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.

Original languageEnglish (US)
Pages (from-to)14867-14874
Number of pages8
JournalJournal of Biological Chemistry
Volume276
Issue number18
DOIs
StatePublished - May 4 2001

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Epoxide Hydrolases
Endothelial cells
Metabolism
Blood Vessels
Endothelial Cells
Acids
Swine
Metabolites
Oxidation
Elongation
Cells
Hypertension
Lipids
Calcium Ionophores
Cell culture
Cytochrome P-450 Enzyme System
Anti-Inflammatory Agents
Cell Culture Techniques
Modulation
Pharmacology

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Pathways of epoxyeicosatrienoic acid metabolism in endothelial cells. Implications for the vascular effects of soluble epoxide hydrolase inhibition. / Fang, Xiang; Kaduce, Terry L.; Weintraub, Neal Lee; Harmon, Shawn; Teesch, Lynn M.; Morisseau, Christophe; Thompson, David A.; Hammock, Bruce D.; Spector, Arthur A.

In: Journal of Biological Chemistry, Vol. 276, No. 18, 04.05.2001, p. 14867-14874.

Research output: Contribution to journalArticle

Fang, Xiang ; Kaduce, Terry L. ; Weintraub, Neal Lee ; Harmon, Shawn ; Teesch, Lynn M. ; Morisseau, Christophe ; Thompson, David A. ; Hammock, Bruce D. ; Spector, Arthur A. / Pathways of epoxyeicosatrienoic acid metabolism in endothelial cells. Implications for the vascular effects of soluble epoxide hydrolase inhibition. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 18. pp. 14867-14874.
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AU - Teesch, Lynn M.

AU - Morisseau, Christophe

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