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

• Published in: Investigative ophthalmology & visual science 2017-10, Vol.58 (12), p.5065-5075
• Main Authors: Qiu, Fangfang, Matlock, Greg, Chen, Qian, Zhou, Kelu, Du, Yanhong, Wang, Xiang, Ma, Jian-Xing
• Format: Article
• Language: English
• Subjects: Animals; Blotting, Western; Capillary Permeability; Choroidal Neovascularization - drug therapy; Choroidal Neovascularization - metabolism; Choroidal Neovascularization - pathology; Disease Models, Animal; Fenofibrate - analogs & derivatives; Fenofibrate - therapeutic use; Fluorescein Angiography; Hypolipidemic Agents - therapeutic use; Injections, Intraperitoneal; Intercellular Adhesion Molecule-1 - metabolism; Leukostasis; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Physiology and Pharmacology; PPAR alpha - agonists; PPAR alpha - genetics; PPAR alpha - metabolism; Rats; Rats, Inbred BN; Receptors, LDL - genetics; Receptors, LDL - metabolism; Tomography, Optical Coherence; Tumor Necrosis Factor-alpha - metabolism; Vascular Endothelial Growth Factor A - metabolism; Wet Macular Degeneration - drug therapy; Wet Macular Degeneration - metabolism; Wet Macular Degeneration - pathology
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.17-22091

This 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. Laser-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. Feno-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. Feno-FA has therapeutic effects on ocular NV in models recapitulating neovascular AMD through a PPARα-dependent mechanism.