Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide

Departments of 1  Biochemistry and 2  Internal Medicine, University of Iowa, Iowa City, Iowa 52242; and 3  Department of Entomology and Cancer Research Center, University of California, Davis, California 95616 Cytochrome P -450 epoxygenase-derived epoxyeicosatrienoic acids (EETs) play an important r...

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Published in:American journal of physiology. Heart and circulatory physiology 2002-12, Vol.283 (6), p.H2306-H2314
Main Authors: Fang, Xiang, Weintraub, Neal L, Oltman, Christine L, Stoll, Lynn L, Kaduce, Terry L, Harmon, Shawn, Dellsperger, Kevin C, Morisseau, Christophe, Hammock, Bruce D, Spector, Arthur A
Format: Article
Language:English
Subjects:
8,11,14-Eicosatrienoic Acid - analogs & derivatives
8,11,14-Eicosatrienoic Acid - chemistry
8,11,14-Eicosatrienoic Acid - metabolism
Cell Line
Chromatography, Liquid
Coronary Vessels - cytology
Coronary Vessels - drug effects
Coronary Vessels - physiology
Culture Media, Conditioned - chemistry
Endothelium, Vascular - chemistry
Endothelium, Vascular - cytology
Endothelium, Vascular - drug effects
Endothelium, Vascular - metabolism
Epoxy Compounds - chemistry
Epoxy Compounds - metabolism
Epoxy Compounds - pharmacology
Fatty Acids, Unsaturated - biosynthesis
Fatty Acids, Unsaturated - chemistry
Fatty Acids, Unsaturated - pharmacology
Humans
Interleukin-8 - biosynthesis
Mass Spectrometry
Oxidation-Reduction
Tumor Necrosis Factor-alpha - pharmacology
Vasodilator Agents - metabolism
Vasodilator Agents - pharmacology
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Summary:Departments of 1  Biochemistry and 2  Internal Medicine, University of Iowa, Iowa City, Iowa 52242; and 3  Department of Entomology and Cancer Research Center, University of California, Davis, California 95616 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 -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- -induced production of IL-8, a proinflammatory cytokine, by HCEC. These findings implicate -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. beta-oxidation; vasorelaxation; inflammation; epoxyeicosatrienoic acid
ISSN:0363-6135
1522-1539
DOI:10.1152/ajpheart.00448.2002