title: Cytochrome P450-generated metabolites derived from ω-3 fatty acids attenuate neovascularization.
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.
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Ryoji
authors: R
authors: Yanai
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Lama
authors: L
authors: Mulki
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Eiichi
authors: E
authors: Hasegawa
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Kimio
authors: K
authors: Takeuchi
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Harry
authors: H
authors: Sweigard
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Jun
authors: J
authors: Suzuki
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Philipp
authors: P
authors: Gaissert
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Demetrios G
authors: DG
authors: Vavvas
authors: Department of Ophthalmology, Yamaguchi University Graduate School of Medicine, 1-1-1 Minami-Kogushi, Ube, Yamaguchi 755-8505, Japan;
authors: Koh-Hei
authors: KH
authors: Sonoda
authors: Lipidomix GmbH, Berlin 13125, Germany; and.
authors: Michael
authors: M
authors: Rothe
authors: Max Delbrück Center for Molecular Medicine, Berlin 13125, Germany.
authors: Wolf-Hagen
authors: WH
authors: Schunck
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114;
authors: Joan W
authors: http://orcid.org/0000-0003-2046-3996
authors: JW
authors: Miller
authors: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114; kip_connor@meei.harvard.edu.
authors: Kip M
authors: KM
authors: Connor
mesh_terms: D000818:Animals; D001095:Arachidonic Acids; D020256:Choroidal Neovascularization / Q000188:drug therapy*; D002853:Chromatography, Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology* / Q000627:therapeutic use; D005434:Flow Cytometry; D005527:Food, Fortified; D015151:Immunoblotting; D061346:Laser Capture Microdissection; D008268:Macular Degeneration / Q000188:drug therapy / Q000503:physiopathology*; D051379:Mice; D047495:PPAR gamma / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry
chemical_list: D001095:Arachidonic Acids; D018076:DNA, Complementary; D015525:Fatty Acids, Omega-3; D047495:PPAR gamma; C070378:17,18-epoxy-5,8,11,14-eicosatetraenoic acid; D003577:Cytochrome P-450 Enzyme System
keywords: PPARγ; adhesion molecules; choroidal neovascularization; epoxy-metabolites; immune cell recruitment