Biomolecular Effects of Jb1 (an IGF-I Peptide Analog) in a Rat Model of Oxygen-Induced Retinopathy

Abstract

Low-serum IGF-I levels at birth is a risk factor for the development of retinopathy of prematurity in extremely LBW infants. We tested the hypothesis that JB1 (an IGF-I analog) prevents oxygen-induced retinopathy in our rat model. Neonatal rats were exposed to 50% oxygen with brief, clustered, hypoxic (12%) episodes from birth to P14. The pups were treated with s.c. injections of 1) JB1 (1 g/d) on P1, P2, and P3 (JB1x3); 2) JB1 (1 g/d) on alternate days from P1 to P13 (JB1x7); or 3) equivalent volume saline. Control littermates were raised in room air (RA) with all conditions identical except for inspired O 2 . Groups were analyzed after hyperoxia/hypoxia (H/H) cycling at P14 or allowed to recover in RA until P21. Systemic and ocular VEGF, soluble VEGFR-1, and IGF-I; retinal vasculature; and gene profile of retinal angiogenesis were assessed. JB1x3 was more effective with associated increases in sVEGFR-1 and decreased retinal pathologies than JB1x7. We conclude that early short-term exposure to systemic JB1 treatment normalizes retinal abnormalities seen with H/H cycling, an effect that may involve sVEGFR-1. (Pediatr Res 69: 135-141, 2011)

Proteomic Profiling of the Retinas in a Neonatal Rat Model of Oxygen-Induced Retinopathy with a Reproducible Ion-Current-Based MS1 Approach

“…14,41 Therefore, most rodent models of ROP use newborn, full term animals exposed to constant high levels of inspired oxygen followed by RA. 10–12,14 In the rat model of OIR used in this study, retinal neovascularization and accumulation of retinal hydrogen peroxide (H 2 O 2 ) level were observed, as demonstrated in recent studies. 17 To achieve a reliable discovery of altered proteins in retinas that are rich in membrane proteins, we have developed a reproducible, extensive, and well-controlled strategy for the profiling of the retinal proteome with multiple biological replicates as we previously reported.…”

“…10–12 Retinal oxygen supply and consumption in those animals are similar to that of primates, thus enabling the use of these models to study the hypoxia-induced retinal neovascularization. 13,14 To promote retinal neovascularization, neonatal rats or mice are usually first exposed to a constant high oxygen level (50%–80%) for more than 1 week.…”

Response of vascular endothelial growth factor and angiogenesis-related genes to stepwise increases in inspired oxygen in neonatal rat lungs

“…Total RNA was extracted from frozen lung samples using RNA Pro solution (MP Bio, Solon, OH) as previously described (37). Cleanup of the RNA was performed using RNEasy mini cleanup kits (Qiagen, Valencia, CA) followed by on-column treatment with DNase I (Qiagen).…”

Neonatal Intermittent Hypoxia, Reactive Oxygen Species, and Oxygen-Induced Retinopathy

“…Hemorrhage occurs as a result of restitution of flow through severely injured microvasculature allowing leakage of intravascular fluids and cells into interstitial spaces. We have shown this phenomenon in our oxygen-induced retinopathy model [19, 63, 108, 109], suggesting that IHR accelerates cell injury.…”

“…This was associated with accumulation of H 2 O 2 , SOD, and HIF1α accumulation during IHR [19]. Our unique model consistently resulted in severe OIR retinal hemorrhage, enlarged vessels, vascular tufts, vascular tortuosity, and vascular overgrowth [19, 63, 108, 109, 139]. Retinal hemorrhage occurring during IHR may be the result of restitution of blood flow through severely injured microvasculature allowing leakage of intravascular fluids and cells into interstitial spaces [140].…”