Abstract
PurposeThis study was designed to evaluate effects of fenofibric acid (Feno-FA), a peroxisome proliferator–activated receptor-alpha (PPARα) agonist, on ocular neovascularization (NV) in models recapitulating neovascular age-related macular degeneration (AMD), and to explore whether the effects are PPARα dependent.MethodsLaser-induced choroidal NV (CNV) in rats and very low-density lipoprotein receptor knockout (Vldlr−/−) mice received daily intraperitoneal injections of Feno-FA or vehicle. Vascular leakage was examined by fundus fluorescein angiography and permeability assay using Evans blue as tracer. In CNV rats, severity of CNV was evaluated by CNV areas and CNV volume. In Vldlr−/− mice, subretinal NV (SRNV) and intraretinal NV (IRNV) were quantified in choroid flat mount and retina flat mount, respectively. Inflammatory factors were measured using Western blotting and retinal leukostasis assay. Further, Pparα−/− mice and age-matched wild-type (WT) mice were used for laser-induced CNV and treated with Feno-FA to explore the underlying mechanism.ResultsFeno-FA significantly reduced vascular leakage in CNV rats and Vldlr−/− mice, reduced CNV volume in laser-induced CNV rats, and suppressed SRNV and IRNV in Vldlr−/− mice. In addition, Feno-FA downregulated the expression of inflammatory factors, including VEGF, TNF-α, and intercellular cell adhesion molecule-1 (ICAM-1), in the eyecups of CNV rats and decreased adherent retinal leukocytes in Vldlr−/− mice. Furthermore, Pparα−/− mice developed more severe CNV compared with WT mice, and PPARα knockout abolished the beneficial effects of Feno-FA on CNV.ConclusionsFeno-FA has therapeutic effects on ocular NV in models recapitulating neovascular AMD through a PPARα-dependent mechanism.
Highlights
FQ and GM contributed to the work presented here and should be regarded as equivalent authors
Neovascular age-related macular degeneration (AMD), responsible for vision loss in approximately 90% of AMD patients, is characterized by choroidal neovascularization (CNV), which refers to the aberrant sprouting of new, immature blood vessels into the subretinal space accompanied by inflammation, vascular leakage, retinal edema, and vision loss.[1,4,5]
We investigated whether peroxisome proliferator–activated receptor-alpha (PPARa) activation using systemic administration of Feno-FA had beneficial effects on ocular NV in models recapitulating some features of neovascular AMD including a laser-induced choroidal NV (CNV) rat model and very low-density lipoprotein receptor knockout (VldlrÀ/À) mice, a genetic subretinal NV (SRNV) and intraretinal NV (IRNV) model
Summary
Laser-induced choroidal NV (CNV) in rats and very low-density lipoprotein receptor knockout (VldlrÀ/À) mice received daily intraperitoneal injections of Feno-FA or vehicle. Vascular leakage was examined by fundus fluorescein angiography and permeability assay using Evans blue as tracer. Inflammatory factors were measured using Western blotting and retinal leukostasis assay. PparaÀ/À mice and age-matched wild-type (WT) mice were used for laser-induced CNV and treated with Feno-FA to explore the underlying mechanism. Male Brown Norway rats (8–10 weeks old; Charles River, Wilmington, MA, USA), VldlrÀ/À mice (postnatal day [P]13– P28), PparaÀ/À mice (8–10 weeks old), and wild-type (WT) C57BL/6J mice (8–10 weeks old; Jackson Laboratories, Bar Harbor, ME, USA) were used. Breeding pairs of VldlrÀ/À mice and PparaÀ/À mice are in the background of C57BL/6J, purchased from Jackson Laboratories. MO, USA), and pupils were dilated with topical administration of 1% cyclopentolate (Wilson, Mustang, OK, USA).
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