Therapeutic Effects of PPAR?± Agonist on Ocular Neovascularization in Models Recapitulating Neovascular Age-Related Macular Degeneration

摘要

Purpose: This study was designed to evaluate effects of fenofibric acid (Feno-FA), a peroxisome proliferatora??activated receptor-alpha (PPAR?±) agonist, on ocular neovascularization (NV) in models recapitulating neovascular age-related macular degeneration (AMD), and to explore whether the effects are PPAR?± dependent. Methods: Laser-induced choroidal NV (CNV) in rats and very low-density lipoprotein receptor knockout (Vldlra??/a??) 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 Vldlra??/a?? 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, Ppar?±a??/a?? mice and age-matched wild-type (WT) mice were used for laser-induced CNV and treated with Feno-FA to explore the underlying mechanism. Results: Feno-FA significantly reduced vascular leakage in CNV rats and Vldlra??/a?? mice, reduced CNV volume in laser-induced CNV rats, and suppressed SRNV and IRNV in Vldlra??/a?? mice. In addition, Feno-FA downregulated the expression of inflammatory factors, including VEGF, TNF-?±, and intercellular cell adhesion molecule-1 (ICAM-1), in the eyecups of CNV rats and decreased adherent retinal leukocytes in Vldlra??/a?? mice. Furthermore, Ppar?±a??/a?? mice developed more severe CNV compared with WT mice, and PPAR?± knockout abolished the beneficial effects of Feno-FA on CNV. Conclusions: Feno-FA has therapeutic effects on ocular NV in models recapitulating neovascular AMD through a PPAR?±-dependent mechanism.