Mammals cannot naturally produce omega-3 (n-3) fatty acids, an essential nutrient found mainly in fish oil, from the more abundant omega-6 (n-6) fatty acids. They must rely on a dietary supply. Lipid-based molecules act as effectors of angiogenesis and inflammation; of particular effectiveness are the eicosanoids, derived from the 20 carbon long chain polyunsaturated fatty acids (LCPUFAs), through the cyclooxygenase (COX) and lipoxygenase (LOX) pathways. Dietary intake of n-3 LCPUFAs has been demonstrated to have anti-angiogenic and anti-inflammatory consequences. Given that LCPUFA tissue status is dependent on dietary intake and the relatively low n-3 LCPUFA intake in western diets, these nutrients are reasonable targets for proliferative retinopathy intervention therapy. In our model retinopathy is induced by subjecting, litters of mouse neonates with mothers to 75% oxygen from P7-P12 and then room air until P17 when retinas are flat mounted after FITC perfusion to fill vessels. To study the effects of n-3 LCPUFAs on retinopathy pregnant mice are fed (from prenatal day 1) a diet enriched with n-3 LCPUFAs or a diet elevated in n-6 LCPUFAs. The effects of COX-2 inhibition on proliferative retinopathy was analyzed by feeding Celecoxib to nursing mouse mothers in the water to achieve a low dose in the pups. There was a -40% reduction in retinal neovascularization and a similar significant decrease in the non-vascularized area at P17 with pups fed from mothers with an enriched n-3 LCPUFA diet verses a n-3 deficient diet, indicating a significant effect of n-3 LCPUFAs on inhibition of retinopathy. In two separate experiments low dose COX-2 inhibition was associated with -50% inhibition of neovascularization at P17 indicating that there is significant potential for COX inhibition to be clinically useful. We seek to further study the role of elevated dietary intake of n-3 LCPUFAs and/or COX-2 inhibition in regulating proliferative retinopathy. Our current data suggests that COX-2 inhibition may be synergistic with n-3 LCPUFA intake. The proposed study is aimed at the identification and characterization of new nutritional and pharmacologic interventions to help prevent the onset of proliferative retinopathy (both diabetic retinopathy and retinopathy of prematurity). We will apply a systems biology molecular mapping approach to establish a new understanding of complex disease mechanisms, to identify novel strategies for the suppression of proliferative retinopathy, and to understand the contribution of lipid signaling pathways in angiogenesis. The potential impact of this study is great since they are nutritional modifications that are well known, they are safe, inexpensive and readily put into practice ? ? ?
| Sapieha, Przemyslaw; Stahl, Andreas; Chen, Jing et al. (2011) 5-Lipoxygenase metabolite 4-HDHA is a mediator of the antiangiogenic effect of ?-3 polyunsaturated fatty acids. Sci Transl Med 3:69ra12 |
| Stahl, Andreas; Connor, Kip M; Sapieha, Przemyslaw et al. (2010) The mouse retina as an angiogenesis model. Invest Ophthalmol Vis Sci 51:2813-26 |
| Chen, Jing; Connor, Kip M; Aderman, Christopher M et al. (2009) Suppression of retinal neovascularization by erythropoietin siRNA in a mouse model of proliferative retinopathy. Invest Ophthalmol Vis Sci 50:1329-35 |
| Chen, Jing; Connor, Kip M; Aderman, Christopher M et al. (2008) Erythropoietin deficiency decreases vascular stability in mice. J Clin Invest 118:526-33 |
| Chen, Jing; Connor, Kip M; Smith, Lois E H (2007) Overstaying their welcome: defective CX3CR1 microglia eyed in macular degeneration. J Clin Invest 117:2758-62 |
| Connor, Kip M; SanGiovanni, John Paul; Lofqvist, Chatarina et al. (2007) Increased dietary intake of omega-3-polyunsaturated fatty acids reduces pathological retinal angiogenesis. Nat Med 13:868-73 |
| Lofqvist, Chatarina; Chen, Jing; Connor, Kip M et al. (2007) IGFBP3 suppresses retinopathy through suppression of oxygen-induced vessel loss and promotion of vascular regrowth. Proc Natl Acad Sci U S A 104:10589-94 |
