@article {836841,
	title = {Cytochrome P450 Oxidase 2C Inhibition Adds to ω-3 Long-Chain Polyunsaturated Fatty Acids Protection Against Retinal and Choroidal Neovascularization.},
	journal = {Arterioscler Thromb Vasc Biol},
	volume = {36},
	number = {9},
	year = {2016},
	month = {2016 Sep},
	pages = {1919-27},
	abstract = {OBJECTIVE: Pathological ocular neovascularization is a major cause of blindness. Increased dietary intake of ω-3 long-chain polyunsaturated fatty acids (LCPUFA) reduces retinal neovascularization and choroidal neovascularization (CNV), but ω-3 LCPUFA metabolites of a major metabolizing pathway, cytochrome P450 oxidase (CYP) 2C, promote ocular pathological angiogenesis. We hypothesized that inhibition of CYP2C activity will add to the protective effects of ω-3 LCPUFA on neovascular eye diseases. APPROACH AND RESULTS: The mouse models of oxygen-induced retinopathy and laser-induced CNV were used to investigate pathological angiogenesis in the retina and choroid, respectively. The plasma levels of ω-3 LCPUFA metabolites of CYP2C were determined by mass spectroscopy. Aortic ring and choroidal explant sprouting assays were used to investigate the effects of CYP2C inhibition and ω-3 LCPUFA-derived CYP2C metabolic products on angiogenesis ex vivo. We found that inhibition of CYP2C activity by montelukast added to the protective effects of ω-3 LCPUFA on retinal neovascularization and CNV by 30\% and 20\%, respectively. In CYP2C8-overexpressing mice fed a ω-3 LCPUFA diet, montelukast suppressed retinal neovascularization and CNV by 36\% and 39\% and reduced the plasma levels of CYP2C8 products. Soluble epoxide hydrolase inhibition, which blocks breakdown and inactivation of CYP2C ω-3 LCPUFA-derived active metabolites, increased oxygen-induced retinopathy and CNV in vivo. Exposure to selected ω-3 LCPUFA metabolites of CYP2C significantly reversed the suppression of both angiogenesis ex vivo and endothelial cell functions in vitro by the CYP2C inhibitor montelukast. CONCLUSIONS: Inhibition of CYP2C activity adds to the protective effects of ω-3 LCPUFA on pathological retinal neovascularization and CNV.},
	issn = {1524-4636},
	doi = {10.1161/ATVBAHA.116.307558},
	author = {Gong, Yan and Fu, Zhongjie and Edin, Matthew L and Liu, Chi-Hsiu and Wang, Zhongxiao and Shao, Zhuo and Fredrick, Thomas W and Saba, Nicholas J and Morss, Peyton C and Burnim, Samuel B and Meng, Steven S and Lih, Fred B and Stephen Lee, Kin Sing and Moran, Elizabeth P and SanGiovanni, John Paul and Hellstr{\"o}m, Ann and Hammock, Bruce D and Zeldin, Darryl C and Smith, Lois E H}
}
