Epoxide hydrolases regulate epoxyeicosatrienoic acid incorporation into coronary endothelial phospholipids.
Cytochrome P-450-derived epoxyeicosatrienoic acids (EETs) are avidly incorporated into and released from endothelial phospholipids, a process that results in potentiation of endothelium-dependent relaxation. EETs are also rapidly converted by epoxide hydrolases to dihydroxyeicosatrienoic acid (DHETs), which are incorporated into phospholipids to a lesser extent than EETs. We hypothesized that epoxide hydrolases functionally regulate EET incorporation into endothelial phospholipids. Porcine coronary artery endothelial cells were treated with an epoxide hydrolase inhibitor, 4-phenylchalcone oxide (4-PCO, 20 micromol/l), before being incubated with (3)H-labeled 14,15-EET (14,15-[(3)H]EET). 4-PCO blocked conversion of 14,15-[(3)H]EET to 14,15-[(3)H]DHET and doubled the amount of radiolabeled products incorporated into cell lipids, with >80% contained in phospholipids. Moreover, pretreatment with 4-PCO before incubation with 14,15-[(3)H]EET enhanced A-23187-induced release of radiolabeled products into the medium. In contrast, 4-PCO did not alter uptake, distribution, or release of [(3)H]arachidonic acid. In porcine coronary arteries, 4-PCO augmented 14,15-EET-induced potentiation of endothelium-dependent relaxation to bradykinin. These data suggest that epoxide hydrolases may play a role in regulating EET incorporation into phospholipids, thereby modulating endothelial function in the coronary vasculature.
Weintraub
N L
NL
Department of Internal Medicine, University of Iowa, Iowa City, Iowa 52242, USA. neal-weintraub@uiowa.edu
Fang
X
X
Kaduce
T L
TL
VanRollins
M
M
Chatterjee
P
P
Spector
A A
AA
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001158:Arteries / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D002478:Cells, Cultured; D002599:Chalcone / Q000031:analogs & derivatives / Q000494:pharmacology; D047188:Chalcones; D003066:Coenzyme A Ligases / Q000037:antagonists & inhibitors; D003331:Coronary Vessels / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000502:physiology*; D006893:Hydroxyeicosatetraenoic Acids / Q000096:biosynthesis; D050356:Lipid Metabolism; D010743:Phospholipids / Q000378:metabolism*; D013552:Swine; D014664:Vasodilation / Q000502:physiology
C107016:14,15-dihydroxyeicosatrienoic acid; C401834:4-phenylchalcone oxide; D047188:Chalcones; D004791:Enzyme Inhibitors; D006893:Hydroxyeicosatetraenoic Acids; D010743:Phospholipids; D016718:Arachidonic Acid; D002599:Chalcone; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D004851:Epoxide Hydrolases; D003066:Coenzyme A Ligases; D015126:8,11,14-Eicosatrienoic Acid; D001920:Bradykinin