title: Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis.
abstract: Neovascular eye diseases including retinopathy of prematurity, diabetic retinopathy and age-related-macular-degeneration are major causes of blindness. Fenofibrate treatment in type 2 diabetes patients reduces progression of diabetic retinopathy independent of its peroxisome proliferator-activated receptor (PPAR)α agonist lipid lowering effect. The mechanism is unknown. Fenofibrate binds to and inhibits cytochrome P450 epoxygenase (CYP)2C with higher affinity than to PPARα. CYP2C metabolizes ω-3 long-chain polyunsaturated fatty acids (LCPUFAs). While ω-3 LCPUFA products from other metabolizing pathways decrease retinal and choroidal neovascularization, CYP2C products of both ω-3 and ω-6 LCPUFAs promote angiogenesis. We hypothesized that fenofibrate inhibits retinopathy by reducing CYP2C ω-3 LCPUFA (and ω-6 LCPUFA) pro-angiogenic metabolites. Fenofibrate reduced retinal and choroidal neovascularization in PPARα-/-mice and augmented ω-3 LCPUFA protection via CYP2C inhibition. Fenofibrate suppressed retinal and choroidal neovascularization in mice overexpressing human CYP2C8 in endothelial cells and reduced plasma levels of the pro-angiogenic ω-3 LCPUFA CYP2C8 product, 19,20-epoxydocosapentaenoic acid. 19,20-epoxydocosapentaenoic acid reversed fenofibrate-induced suppression of angiogenesis ex vivo and suppression of endothelial cell functions in vitro. In summary fenofibrate suppressed retinal and choroidal neovascularization via CYP2C inhibition as well as by acting as an agonist of PPARα. Fenofibrate augmented the overall protective effects of ω-3 LCPUFAs on neovascular eye diseases.
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Zhongjie
authors.initials: Z
authors.lastname: Fu
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Edin
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Ye
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Raffael G
authors.initials: RG
authors.lastname: Liegl
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Zhongxiao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Chi-Hsiu
authors.initials: CH
authors.lastname: Liu
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Samuel B
authors.initials: SB
authors.lastname: Burnim
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States.
authors.forename: Steven S
authors.initials: SS
authors.lastname: Meng
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States.
authors.forename: Fred B
authors.initials: FB
authors.lastname: Lih
authors.affiliation: Section on Nutritional Neurosciences, Laboratory of Membrane Biophysics and Biochemistry, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: John Paul
authors.initials: JP
authors.lastname: SanGiovanni
authors.affiliation: Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States.
authors.forename: Darryl C
authors.initials: DC
authors.lastname: Zeldin
authors.affiliation: Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg 40530, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Hellström
authors.affiliation: Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States. Electronic address: lois.smith@childrens.harvard.edu.
authors.forename: Lois E H
authors.initials: LEH
authors.lastname: Smith
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D020256:Choroidal Neovascularization / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D015525:Fatty Acids, Omega-3 / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D047493:PPAR alpha / Q000378:metabolism; D012164:Retinal Diseases / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D015861:Retinal Neovascularization / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D015398:Signal Transduction
chemical_list: D020533:Angiogenesis Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D047493:PPAR alpha; C400322:cytochrome P-450 CYP2C subfamily; D003577:Cytochrome P-450 Enzyme System; D011345:Fenofibrate
keywords: Choroidal neovascularization; Cytochrome P450 epoxygenase 2C; Fenofibrate; Omega-3 long-chain polyunsaturated fatty acids; Retinal neovascularization; Retinopathy