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

Ryoji Yanai, Lama Mulki, Eiichi Hasegawa, Kimio Takeuchi, Harry Sweigard, Jun Suzuki, Philipp Gaissert, Demetrios G. Vavvas, Kohei Sonoda, Michael Rothe, Wolf Hagen Schunck, Joan W. Miller, Kip M. Connor

Research output: Contribution to journalArticle

36 Citations (Scopus)

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 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 neovascular disease and show promising therapeutic potential for resolution of neovascular AMD.

Original languageEnglish
Pages (from-to)9603-9608
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number26
DOIs
Publication statusPublished - Jul 1 2014

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Unsaturated Fatty Acids
Cytochrome P-450 Enzyme System
Fatty Acids
Macular Degeneration
Eicosanoids
Angiogenesis Modulating Agents
Lipids
Acids
Eicosapentaenoic Acid
Eye Diseases
Docosahexaenoic Acids
Cell Adhesion Molecules
Blindness
Dietary Supplements
Developed Countries
Anti-Inflammatory Agents
Pharmacology
Serum
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

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Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization. / Yanai, Ryoji; Mulki, Lama; Hasegawa, Eiichi; Takeuchi, Kimio; Sweigard, Harry; Suzuki, Jun; Gaissert, Philipp; Vavvas, Demetrios G.; Sonoda, Kohei; Rothe, Michael; Schunck, Wolf Hagen; Miller, Joan W.; Connor, Kip M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 111, No. 26, 01.07.2014, p. 9603-9608.

Research output: Contribution to journalArticle

Yanai, R, Mulki, L, Hasegawa, E, Takeuchi, K, Sweigard, H, Suzuki, J, Gaissert, P, Vavvas, DG, Sonoda, K, Rothe, M, Schunck, WH, Miller, JW & Connor, KM 2014, 'Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization', Proceedings of the National Academy of Sciences of the United States of America, vol. 111, no. 26, pp. 9603-9608. https://doi.org/10.1073/pnas.1401191111
Yanai, Ryoji ; Mulki, Lama ; Hasegawa, Eiichi ; Takeuchi, Kimio ; Sweigard, Harry ; Suzuki, Jun ; Gaissert, Philipp ; Vavvas, Demetrios G. ; Sonoda, Kohei ; Rothe, Michael ; Schunck, Wolf Hagen ; Miller, Joan W. ; Connor, Kip M. / Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization. In: Proceedings of the National Academy of Sciences of the United States of America. 2014 ; Vol. 111, No. 26. pp. 9603-9608.
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AU - Suzuki, Jun

AU - Gaissert, Philipp

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