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

作者：Ryoji Yanai, Lama Mulki, Eiichi Hasegawa, Kimio Takeuchi, Harry Sweigard, Jun Suzuki, Philipp Gaissert, Demetrios G. Vavvas, Koh‐Hei Sonoda, Michael Rothe, Wolf-Hagen Schunck, Joan W. Miller, Kip M. Connor · 发表于：Proceedings of the National Academy of Sciences · 年份：2014 · DOI：10.1073/pnas.1401191111 · 被引用次数：79 · 研究领域：Eicosanoids and Hypertension Pharmacology、Fatty Acid Research and Health、Peroxisome Proliferator-Activated Receptors

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 ω-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 ω-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 ω-3 LCPUFAs, were identified as key lipid mediators of disease resolution. We conclude that CYP-derived bioactive lipid metabolites from ω-3 LCPUFAs are potent inhibitors of intraocular neovascula...