Dietary Intake of -3 Polyunsaturated Fatty Acids Promotes an Anti-Angiogenic Lipidomic Profile in the Retina

Abstract

Purpose: : Vaso-proliferative retinopathies account for the principal causes of blindness across all age groups. These diseases present an inflammatory component in part mediated by potent lipid derived effectors such as eicosanoid products of the cyclooxygenses (COX-1 and 2) and lipoxygenase (5-, 12- and 15-LO) pathways. Previous work from our group demonstrated that diets enriched for ω-3 polyunsaturated fatty acids (PUFAs) versus ω-6 PUFAs (mimicking Japanese versus Western diets) substantially improve disease outcome in a mouse model of proliferative retinopathy. To elucidate the effectors of this beneficial diet, we performed lipidomic profiles on retinas from ω-3 PUFA enriched diets versus ω-6 PUFAs rich diets with a specific focus on products of the LO pathway for which ω-3 and ω-6 PUFAs are substrates.

Methods: : Mouse mothers, at delivery, were fed isocaloric diets enriched in either ω-3 PUFAs or conversely ω-6 PUFAs. Proliferative retinopathy was mimicked in an oxygen-induced mouse model where pups were exposed to 75% O2 from postnatal day (P) 7 to P12 and returned to room air for 5 days. Retinas were collected and lipid derived mediators analysed by LC/MS/MS-based lipidomics.

Results: : Retinal lipidomic analysis of animals subjected to OIR revealed that dietary supplementation with ω-3 PUFA lead to a 2-fold reduction in the pro-inflammatory LOX-5 product 5-hydroxyeicosatetraenoic acid (HETE) and a 3-fold reduction in the mitogenic LOX-12 product 12-HETE (when compared to ω-6 PUFA rich diets) while the anti-inflammatory LOX-15 product, 15-HETE was not significantly affected. Consistent with the anti-angiogenic qualities of an ω-3 rich diet, a 2-fold increase in the potent anti-inflammatory DHA product, D- series resolvin 17-HDHA was observed.

Conclusions: : The lipidomic analysis reported in this study reveals that diets enriched in ω-3 PUFAs promote anti-inflammatory lipidomic profiles within the retina. This is achieved by reducing levels of inflammatory lipid mediators (such as HETEs) in concert with increasing the production of anti-inflammatory products (such as D-series resolvins). These findings provide the ground work for selecting lipid mediators for therapeutic applications to curtail ocular neovascularization.

Keywords: retinal neovascularization • retina • lipids