Omega-3 long chain polyunsaturated fatty acids promote choroidal neovessel regression

Abstract

Purpose: Age-related macular degeneration (AMD) is the primary cause of blindness in elderly individuals of industrialized countries. Prospective clinical studies have indicated that dietary intake of omega (ω)-3 long-chain polyunsaturated fatty acids (LCPUFAs) may have a protective effect against AMD. This study characterizes the effects of dietary intake of ω-3 and ω-6 LCPUFAs in a mouse model of AMD.

Methods: The present studies adhered to ARVO’s Statement for the Use of Animals in Ophthalmic and Vision Research. C57BL/6 mice were fed a diet enriched with either ω-3 or ω-6 LCPUFAs for 2 weeks prior to choroidal neovascularization (CNV) induction by photocoagulation using a 532-nm laser. CNV development was evaluated by Fluorescein Angiography (FA), Optical Coherence Tomography (OCT), and choroidal flatmount (CFM). The primary eicosanoids and their downstream metabolites were analyzed by LC MS/MS lipidomics. Expression of ICAM-1, E-selectin, and VEGF in the retina, choroid, or laser-captured CNV were evaluated by RTPCR and immunoblot analysis. Macrophage invasion was evaluated in Cx3cr1GFP/+ mice. Leukocyte rolling velocity was analyzed using the autoperfused microflow chamber assay.

Results: Both OCT and CFM revealed the CNV size were significantly reduced, and FA grading showed significantly less leakage in the ω-3-fed-mice compared with the ω-6-fed mice. The concentrations of the principal ω-3 LCPUFAs (EPA and DHA) were significantly increased in serum of ω-3-fed mice. The serum levels of AA-derived eicosanoids were significantly reduced, whereas those of EPA-derived- and DHA-derived eicosanoids were significantly increased in ω-3-fed mice. The mRNA expression and abundance of protein of ICAM-1 and E-selectin in the retina or choroid after CNV induction were significantly reduced in ω-3-fed mice. The rolling velocity of leucocytes on the combination of P-selectin and ICAM-1 coated chamber was significantly greater in ω-3-fed mice. The abundance of VEGF protein in both the retina and choroid was significantly reduced in ω-3-fed mice.

Conclusions: We demonstrate that dietary supplementation of ω-3 LCPUFAs mediate choroidal neovessel regression. A clear understanding of the mechanisms of these molecules in AMD could bring a major shift in our approach to disease treatment. Currently there is an urgent need for safe nutritional or pharmacological interventions for the treatment and ideally the prevention of AMD.

Keywords: 412 age-related macular degeneration • 583 lipids • 453 choroid: neovascularization