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Yan Gong, Zhongjie Fu, Matthew Edin, Nicholas Saba, Thomas Fredrick, Peyton Morss, Samuel Burnim, Steven Meng, Darryl Zeldin, Lois E H Smith; Fenofibrate Suppresses Retinal Pathologic Neovascularization via Inhibiting Cytochrome P450 Epoxygenase 2C Activity. Invest. Ophthalmol. Vis. Sci. 2016;57(12):4529.
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© ARVO (1962-2015); The Authors (2016-present)
Fenofibrate reduces cholesterol levels via proliferator-activated receptor alpha (PPARα) activation in diabetic patients with cardiovascular disease and has a direct effect on retinopathy through activation of PPARα in animal studies. In a subanalysis of the effect of fenofibrate on retinopathy in both the Fenofibrate Intervention and Event Lowering in Diabetes study and the Action to Control Cardiovascular Risk in Diabetes Eye trial with ~10,000 type 2 diabetic patients either there was ~40% reduction in progression of retinopathy with fenofibrate treatment independent of its lipid lowering effect. Because fenofibrate is a potent inhibitor of Cytochrome P450 epoxygenase 2C8 (CYP2C8) with ~10 times higher affinity compared to PPARα, we postulated that fenofibrate inhibits pathological angiogenesis and protects against retinopathy in part through through CYP2C inhibition as well as PPARα activation. In this study we find CYP2C inhibition with fenofibrate suppresses retinopathy.
The mouse oxygen-induced retinopathy (OIR) model was used to investigate in vivo retinal neovascularization. Levels of CYP2C8 metabolites in plasma were determined by liquid chromatography and tandem mass spectroscopy. The anti-angiogenic role of fenofibrate and regulation of endothelial cell behaviors were evaluated in an ex vivo aortic ring sprouting assay, and endothelial cell tubule formation and migration assays in vitro.
Fenofibrate inhibits neovascularization in both wild-type and PPARα knock-out mice, suggesting that fenofibrate inhibits pathological angiogenesis in part through a PPARα-independent pathway in addition to its well-known PPARα agonist role. Fenofibrate suppresses neovascularization without PPARα activation in Tie2-driven CYP2C8 over-expressing mice. Fenofibric acid, the bioactive metabolite of fenofibrate, inhibits aortic ring sprouting, endothelial cell tubule formation and migration; CYP2C8 metabolites rescue its inhibitory effects.
Fenofibrate suppresses retinal pathologic neovascularization in part via CYP2C inhibition. Cyp2C inhibition may be a viable approach for inhibition of proliferative retinopathy and other diseases with pathological angiogenesis.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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