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Yan Gong, Zhuo Shao, Zhongjie Fu, Matthew Edin, Lucy P Evans, Hannah H Bogardus, Katherine T Tian, Jing Chen, Darryl C Zeldin, Lois Smith; Cytochrome P450 Epoxygenase 2C8 Metabolites of ω3-Long-Chain Polyunsaturated Fatty Acids Increase Pathologic Neovascularization in Mouse Retina. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5393.
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Pathologic neovascularization during oxygen-induced retinopathy (OIR) is suppressed by dietary ω3-long-chain polyunsaturated fatty acids (ω3LCPUFAs) through anti-angiogenic metabolites of cyclooxygenase and lipoxygenase. ω3LCPUFAs can also be metabolized by Cytochrome P450 epoxygenase 2C8 (CYP2C8), producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to trans-dihydrodiols. The purpose of this study is to identify the effects of CYP2C8 and sEH, as well as their metabolites, on neovascularization in mouse retina.
The mouse model of OIR was used to investigate retinal neovascularization. Levels of CYP2C8 and sEH metabolites in plasma and retina were determined by liquid chromatography and tandem mass spectroscopy. The angiogenic role of CYP2C8 and its metabolites, as well as the angiogenic role of sEH, were evaluated in OIR and also corroborated in aortic ring assays from Tie2-driven-CYP2C8-overexpressing (Tie2-CYP2C8-Tg) and in Tie2-driven-sEH-overexpressing (Tie2-sEH-Tg) mice.
CYP2C (expressed in monocytes/macrophages) is up-regulated in OIR while sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a ω3LCPUFA-enriched diet, Tie2-CYP2C8-Tg mice show increased retinal neovascularization, associated with increased 19,20-EDP concentration in plasma and increased retinal epoxide:diol ratio. In Tie2-sEH-Tg mice, retinal neovascularization is increased, accompanied by decreased 19,20-EDP concentration in plasma and decreased retinal epoxide:diol ratio. Conditional overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls.
Our results suggest that CYP2C metabolites of ω3LCPUFA promote pathologic angiogenesis in mouse retina. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
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