Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis

Yan Gong; Zhuo Shao; Zhongjie Fu; Matthew L. Edin; Ye Sun; Raffael G. Liegl; Zhongxiao Wang; Chi-Hsiu Liu; Samuel B. Burnim; Steven S. Meng; Fred B. Lih; John Paul SanGiovanni; Darryl C. Zeldin; Ann Hellström; Lois E.H. Smith

doi:10.1016/j.ebiom.2016.09.025

EBioMedicine (Nov 2016)

Fenofibrate Inhibits Cytochrome P450 Epoxygenase 2C Activity to Suppress Pathological Ocular Angiogenesis

Yan Gong,
Zhuo Shao,
Zhongjie Fu,
Matthew L. Edin,
Ye Sun,
Raffael G. Liegl,
Zhongxiao Wang,
Chi-Hsiu Liu,
Samuel B. Burnim,
Steven S. Meng,
Fred B. Lih,
John Paul SanGiovanni,
Darryl C. Zeldin,
Ann Hellström,
Lois E.H. Smith

Affiliations

Yan Gong: 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

DOI: https://doi.org/10.1016/j.ebiom.2016.09.025
Journal volume & issue: Vol. 13, no. C
pp. 201 – 211

Abstract

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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.

Published in EBioMedicine

ISSN: 2352-3964 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Medicine (General)
Website: http://www.journals.elsevier.com/ebiomedicine/

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