title: Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide.
abstract: Cytochrome P-450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) play an important role in the regulation of vascular reactivity and function. Conversion to the corresponding dihydroxyeicosatrienoic acids (DHETs) by soluble epoxide hydrolases is thought to be the major pathway of EET metabolism in mammalian vascular cells. However, when human coronary artery endothelial cells (HCEC) were incubated with (3)H-labeled 14,15-EET, chain-shortened epoxy fatty acids, rather than DHET, were the most abundant metabolites. After 4 h of incubation, 23% of the total radioactivity remaining in the medium was converted to 10,11-epoxy-hexadecadienoic acid (16:2), a product formed from 14,15-EET by two cycles of beta-oxidation, whereas only 15% was present as 14,15-DHET. Although abundantly present in the medium, 10,11-epoxy-16:2 was not detected in the cell lipids. Exogenously applied (3)H-labeled 10,11-epoxy-16:2 was neither metabolized nor retained in the cells, suggesting that 10,11-epoxy-16:2 is a major product of 14,15-EET metabolism in HCEC. 10,11-Epoxy-16:2 produced potent dilation in coronary microvessels. 10,11-Epoxy-16:2 also potently inhibited tumor necrosis factor-alpha-induced production of IL-8, a proinflammatory cytokine, by HCEC. These findings implicate beta-oxidation as a major pathway of 14,15-EET metabolism in HCEC and provide the first evidence that EET-derived chain-shortened epoxy fatty acids are biologically active.
authors.affiliation: Department of Biochemistry, University of Iowa, Iowa City 52242, USA. xiang-fang@uiowa.edu
authors.forename: Xiang
authors.initials: X
authors.lastname: Fang
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.forename: Christine L
authors.initials: CL
authors.lastname: Oltman
authors.forename: Lynn L
authors.initials: LL
authors.lastname: Stoll
authors.forename: Terry L
authors.initials: TL
authors.lastname: Kaduce
authors.forename: Shawn
authors.initials: S
authors.lastname: Harmon
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Dellsperger
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Arthur A
authors.initials: AA
authors.lastname: Spector
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D002853:Chromatography, Liquid; D003331:Coronary Vessels / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D017077:Culture Media, Conditioned / Q000737:chemistry; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004852:Epoxy Compounds / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000096:biosynthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis; D013058:Mass Spectrometry; D010084:Oxidation-Reduction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014665:Vasodilator Agents / Q000378:metabolism* / Q000494:pharmacology
chemical_list: C469614:10,11-epoxy-hexadecadienoic acid; D017077:Culture Media, Conditioned; D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D015126:8,11,14-Eicosatrienoic Acid