5-Lipoxygenase Mediates The Anti-angiogenic Effects Of -3 PUFAs In Proliferative Retinopathy

Abstract

Purpose: : We have previously demonstrated that diets enriched in omega-3 polyunsaturated fatty acids (ω-3 PUFAs) effectively reduce pathological neovascularization (NV) in a mouse model of oxygen-induced retinopathy (OIR). However, the primary mechanisms by which ω-3 PUFAs impede pathological angiogenesis are incompletely understood.

Methods: : Proliferative retinopathy was induced using the OIR mouse model. Diets enriched in ω-3 or ω-6 PUFAs were provided from delivery onwards in mice devoid of specific members of the cycloxygenase (COX) and lipoxygenase (LOX) families (COX-1, COX-2, 5-LOX and 12/15-LOX). Pathological NV formation was assessed in all knock-out strains at P17, lipid metabolites were measured using LC/MS/MS-based lipidomics and PPARγ expression was quantified using qPCR and Western blot.

Results: : WT mice fed ω-3 PUFAs show ~50% less retinal NV compared to ω-6 controls (p<0.0001). Genetic knock-out of COX-1, COX-2 or 12/15-LOX did not change the beneficial effect of ω-3 PUFAs. In contrast, the anti-angiogenic effect of ω-3 PUFAs was completely abolished in mice lacking the 5-LOX enzyme. 5-LOX -/- mice on ω-3 PUFAs showed NV areas that were identical to ω-6 controls and 57% greater than in ω-3 WT controls (p<0.01). Analysis of 5-LOX dependent metabolites identified specific oxydized ω-3 PUFA derivatives as direct anti-angiogenic mediators acting on retinal endothelial cells via activation of the PPARγ receptor.

Conclusions: : This study identifies a central role for the lipid-processing enzyme 5-LOX in mediating the anti-angiogenic effects of ω-3 PUFAs in proliferative retinopathy. 5-LOX metabolites activate PPARγ receptors in retinal endothelial cells and elicit a direct anti-angiogenic response that is independent of inflammatory activation.

Keywords: retinal neovascularization • retinopathy of prematurity • diabetic retinopathy