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.
Copyright © 2012 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, N.I.H., Intramural
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Research Support, Non-U.S. Gov't
MeSH terms
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8,11,14-Eicosatrienoic Acid / analogs & derivatives
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8,11,14-Eicosatrienoic Acid / metabolism
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Acute Disease
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Animals
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Cyclooxygenase Inhibitors / pharmacology
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Cytochrome P-450 CYP2J2
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P-450 Enzyme System / metabolism*
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Endothelium, Vascular / drug effects
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Endothelium, Vascular / metabolism*
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Endothelium, Vascular / pathology
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Endotoxins / pharmacology
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Epoxide Hydrolases / antagonists & inhibitors*
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Epoxide Hydrolases / deficiency
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Female
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Gene Expression Regulation
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Indomethacin / pharmacology
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Inflammation / chemically induced
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Inflammation / enzymology
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Inflammation / prevention & control
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Liver / drug effects
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Liver / enzymology*
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Liver / pathology
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Lung / drug effects
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Lung / enzymology*
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Lung / pathology
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Male
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Mice
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Mice, Transgenic
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Peroxidase / genetics
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Peroxidase / metabolism
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Prostaglandin-Endoperoxide Synthases / genetics
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Prostaglandin-Endoperoxide Synthases / metabolism*
Substances
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14,15-dihydroxyeicosatrienoic acid
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Cyclooxygenase Inhibitors
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Endotoxins
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14,15-epoxy-5,8,11-eicosatrienoic acid
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Cytochrome P-450 Enzyme System
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Peroxidase
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Cytochrome P-450 CYP2J2
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Prostaglandin-Endoperoxide Synthases
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Epoxide Hydrolases
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Ephx2 protein, mouse
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8,11,14-Eicosatrienoic Acid
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Indomethacin