title: Dual modulation of cyclooxygenase and CYP epoxygenase metabolism and acute vascular inflammation in mice.
abstract: Cyclooxygenase (COX)-derived prostaglandins and cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids are important regulators of inflammation; however, functional interactions between these pathways in the regulation of vascular inflammation in vivo have not been studied. We investigated the relative and additive effects of endothelial CYP2J2 overexpression (Tie2-CYP2J2-Tr), global sEH disruption (Ephx2(-/-)), and pharmacologic COX inhibition with indomethacin on the acute vascular inflammatory response to endotoxin in mice. Compared to vehicle-treated wild-type C57BL/6 controls, induction of myeloperoxidase (MPO) activity in lung and liver was similarly attenuated in Tie2-CYP2J2-Tr mice, Ephx2(-/-) mice and wild-type mice treated with moderate dose indomethacin. Dual modulation of both pathways, however, did not produce an additive anti-inflammatory effect. These findings demonstrate that both COX and CYP epoxygenase-mediated eicosanoid metabolism are important regulators of the acute vascular inflammatory response in vivo, and suggest that the anti-inflammatory effects of modulating each pathway may be mediated, at least in part, by overlapping mechanisms.
authors.affiliation: Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Akinyemi
authors.initials: A
authors.lastname: Oni-Orisan
authors.forename: Yangmei
authors.initials: Y
authors.lastname: Deng
authors.forename: Robert N
authors.initials: RN
authors.lastname: Schuck
authors.forename: Katherine N
authors.initials: KN
authors.lastname: Theken
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.forename: Kimberly
authors.initials: K
authors.lastname: Molnar
authors.forename: Laura
authors.initials: L
authors.lastname: DeGraff
authors.forename: Kenneth B
authors.initials: KB
authors.lastname: Tomer
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.forename: Craig R
authors.initials: CR
authors.lastname: Lee
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D000208:Acute Disease; D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D000090762:Cytochrome P-450 CYP2J2; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D004731:Endotoxins / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000172:deficiency; D005260:Female; D005786:Gene Expression Regulation; D007213:Indomethacin / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control; D008099:Liver / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009195:Peroxidase / Q000235:genetics / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*
chemical_list: C107016:14,15-dihydroxyeicosatrienoic acid; D016861:Cyclooxygenase Inhibitors; D004731:Endotoxins; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D003577:Cytochrome P-450 Enzyme System; D009195:Peroxidase; D000090762:Cytochrome P-450 CYP2J2; D011451:Prostaglandin-Endoperoxide Synthases; D004851:Epoxide Hydrolases; C518648:Ephx2 protein, mouse; D015126:8,11,14-Eicosatrienoic Acid; D007213:Indomethacin