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1 Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA
2 Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA; Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
3 Department of Ophthalmology, Medical College of Georgia, Augusta, GA, USA
4 Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA
5 Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA; Vascular Biology Center, Medical College of Georgia, Augusta, GA, USA; Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta, GA, USA
* To whom correspondence should be addressed. E-mail: rcaldwel{at}mail.mcg.edu.
Hyperoxia exposure induces capillary endothelial cell apoptosis in the developing retina, leading to vaso-obliteration followed by proliferative retinopathy. Previous in vivo studies have shown that endothelial nitric oxide synthase (NOS3) and peroxynitrite are important mediators of the vaso-obliteration. Now we have investigated the relationship between hyperoxia, NOS3, peroxynitrite, and endothelial cell apoptosis by in vitro experiments using bovine retinal endothelial cells (BREC). We found that BREC exposed to 40% oxygen (hyperoxia) for 48 hours underwent apoptosis associated with activation of caspase-3 and cleavage of the caspase substrate poly ADP ribose polymerase. Hyperoxia-induced apoptosis was associated with increased formation of nitric oxide (NO), peroxynitrite, and superoxide anion and was blocked by treatment with uric acid, L-NAME, or superoxide dismutase. Analyses of the PI-3 kinase/AKT kinase survival pathway in cells directly treated with peroxynitrite revealed inhibition of VEGF- and bFGF-induced activation of AKT kinase. These results suggest that hyperoxia-induced formation of peroxynitrite induces BREC apoptosis by crippling key survival pathways, and that blocking peroxynitrite formation prevents apoptosis. These data may have important clinical implications for infants at risk of retinopathy of prematurity.
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