Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization

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Item Type:	Article
Title:	Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization
Creators Name:	Yanai, R., Mulki, L., Hasegawa, E., Takeuchi, K., Sweigard, H., Suzuki, J., Gaissert, P., Vavvas, D.G., Sonoda, K.H., Rothe, M., Schunck, W.H., Miller, J.W. and Connor, K.M.
Abstract:	Ocular neovascularization, including age-related macular degeneration (AMD), is a primary cause of blindness in individuals of industrialized countries. With a projected increase in the prevalence of these blinding neovascular diseases, there is an urgent need for new pharmacological interventions for their treatment or prevention. Increasing evidence has implicated eicosanoid-like metabolites of long-chain polyunsaturated fatty acids (LCPUFAs) in the regulation of neovascular disease. In particular, metabolites generated by the cytochrome P450 (CYP)-epoxygenase pathway have been shown to be potent modulators of angiogenesis, making this pathway a reasonable previously unidentified target for intervention in neovascular ocular disease. Here we show that dietary supplementation with {omega}-3 LCPUFAs promotes regression of choroidal neovessels in a well-characterized mouse model of neovascular AMD. Leukocyte recruitment and adhesion molecule expression in choroidal neovascular lesions were down-regulated in mice fed {omega}-3 LCPUFAs. The serum of these mice showed increased levels of anti-inflammatory eicosanoids derived from eicosapentaenoic acid and docosahexaenoic acid. 17,18-epoxyeicosatetraenoic acid and 19,20-epoxydocosapentaenoic acid, the major CYP-generated metabolites of these primary {omega}-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from {omega}-3 LCPUFAs are potent inhibitors of intraocular neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.
Keywords:	Choroidal Neovascularization, Immune Cell Recruitment, PPAR{gamma}, Adhesion Molecules, Epoxy-Metabolites, Animals, Mice
Source:	Proceedings of the National Academy of Sciences of the United States of America
ISSN:	0027-8424
Publisher:	National Academy of Sciences
Volume:	111
Number:	26
Page Range:	9603-9608
Date:	1 July 2014
Official Publication:	https://doi.org/10.1073/pnas.1401191111
PubMed:	View item in PubMed

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