Human coronary endothelial cells convert 14,15-EET to a biologically active chain-shortened epoxide.
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.
Fang
Xiang
X
Department of Biochemistry, University of Iowa, Iowa City 52242, USA. xiang-fang@uiowa.edu
Weintraub
Neal L
NL
Oltman
Christine L
CL
Stoll
Lynn L
LL
Kaduce
Terry L
TL
Harmon
Shawn
S
Dellsperger
Kevin C
KC
Morisseau
Christophe
C
Hammock
Bruce D
BD
Spector
Arthur A
AA
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
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