Abstract 20225: Dietary Supplementation with Argine-Glutamine (Arg-Gln) Dipeptide Reduces Pathological Neovascularization (NV) and Promotes Retinal Vessel Re-growth (VR) in Mouse Model Of Retinopathy of Prematurity (ROP)
Objective: Retinopathy of prematurity (ROP) has two critical phases, vessel loss followed by hypoxia-driven destructive neovascularization. Stress-induced downregulation of retinal elongases translates into a decrease in total retinal docosahexaenoic acid (DHA) (Tikhonenko M 2010). We studied the influence of Arg-Gln on changes in retinal DHA and on vascular loss, vascular regrowth after injury, and hypoxia-induced pathological neovascularization in a mouse model of oxygen-induced retinopathy (OIR).
Methods: 7-day old pups were placed in 75% oxygen for five days. Pups were returned to room air on postnatal day 12 (P12) and supplemented by oral gavage twice daily with Arg-Gln (5 g/kg/d), DHA (2.5 g/kg/d), Arg-Gln + DHA, or vehicle through P17. On P17, pups were sacrificed and perfused with FITC-labeled dextran. Retinas were assessed for NV by enumeration of pre-retinal endothelial cells and intra-retinal vascular density (VD). DHA levels were measured by reverse-phase high-performance liquid chromatography in control, OIR affected and OIR affected treated with DHA or Arg-Gln retinas.
Results: Compared to vehicle, pre-retinal NV was reduced by 61% and 51% with Arg-Gln or DHA (p<0.05 both), with a 69% reduction observed for Arg-Gln + DHA (p<0.05). All treatments reduced vaso-obliteration vs. vehicle (32% vs. 5.2%, p<0.05). Arg-Gln, alone or with DHA, promoted intra-retinal VD vs. vehicle (73–76% vs. 53%). Intravitreal injections of Arg-Gln as well as treatment of the animals with DHA, normalized DHA levels in the OIR retinas (p<0.05 for all conditions compared to untreated controls). The effect of the combination of DHA and Arg-Gln treatment was similar to individual treatments.
Conclusions: We show that increasing Arg-Gln levels decreased the avascular area of the retina by increasing vessel regrowth after injury, thereby reducing the hypoxic stimulus for neovascularization. The protective effect of Arg-Gln was mediated, in part, through correcting the levels of DHA to normal. This is the first study demonstrating hyperoxia-induced changes in retinal fatty acid metabolism. Normalization of retinal fatty acid levels by Arg-Gln or by dietary means potentially modulates expression of elongases and represents a future therapy for ROP.
- © 2010 by American Heart Association, Inc.