Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Zhuo Shao
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Zhongjie Fu
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Matthew L. Edin
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
Ye Sun
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Raffael G. Liegl
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Zhongxiao Wang
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Chi-Hsiu Liu
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Samuel B. Burnim
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Steven S. Meng
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
Fred B. Lih
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
John Paul SanGiovanni
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
Darryl C. Zeldin
Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, United States
Ann Hellström
Department of Ophthalmology, Sahlgrenska Academy at University of Gothenburg, Gothenburg 40530, Sweden
Lois E.H. Smith
Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, MA 01248, United States
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.
