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Fangfang Qiu, H. Greg Matlock, Qian Chen, Yanhong Du, Kelu Zhou, Jian-Xing (Jay) Ma; Therapeutic Effects of PPARα Agonist on Experimental Neovascular Age-Related Macular Degeneration. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1925. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Our previous studies demonstrated that fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPARα) agonist, has therapeutic effects on diabetic retinopathy and ischemia-induced retinal neovascularization (NV). This study was designed to investigate the effect of fenofibrate acid (Feno-FA), the active metabolite of fenofibrate, on neovascular age-related macular degeneration (AMD), and to explore whether the effect is PPARα dependent.
Laser-induced choroidal neovascularization (CNV) in rats and very low-density lipoprotein receptor (VLDLR) knockout (KO) mice were used as neovascular AMD models. Animals were intraperitoneally injected with Feno-FA (25 mg/kg body weight/day) or vehicle, beginning at the same day as the laser treatment in CNV rats for two weeks, and from P13-P28 in VLDLR KO mice. In CNV rats, vascular leakage from CNV was examined by fundus fluorescein angiography (FFA). Severity of CNV were evaluated by NV areas measured in choroidal flat mount and CNV volume measured with optical coherence tomography (OCT). In VLDLR KO mice, retina vascular leakage was examined by FFA and permeability using Evans blue as tracer. Severity of CNV was evaluated by sub-retinal NV (SRNV) numbers measured in choroidal flat mount, and intra-retinal NV (IRNV) numbers in retinal flat mount. Levels of inflammatory factors in eyecups of CNV rats were determined by Western blotting, and adherent leukocytes in retinal vasculature in VLDLR KO mice were quantified using leukostasis assay. Further, PPARα KO mice and age-matched wild-type (WT) mice were used to induce CNV by laser, and treated with Feno-FA daily, and then CNV volume was measured by OCT at 7 days after treatment.
Feno-FA significantly ameliorated vascular leakage in CNV rats and VLDLR KO mice, and reduced the severity of CNV in CNV rats, and numbers of SRNV and IRNV in VLDLR KO mice. In addition, Feno-FA downregulated the expression of inflammatory factors including VEGF, TNF-α and ICAM-1 in the eyecups of CNV rats, and reduced adherent leukocytes in the retina of VLDLR KO mice. Furthermore, PPARα KO mice developed more severe CNV, compared with WT mice, and PPARα KO abolished the Feno-FA’s beneficial effects on CNV.
PPARα agonist has a potential therapeutic effect on neovascular AMD, and this effect is via a PPARα-dependent mechanism.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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