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The Journal of Neuroscience, May 15, 2002, 22(10):3987-3993
Inducible Nitric Oxide Synthase Mediates Retinal Apoptosis in Ischemic Proliferative Retinopathy
Florian Sennlaub1, 2, Yves Courtois1, and Olivier Goureau1 1 Développement, Vieillissement et Pathologie de la Rétine, Institut National de la Santé et de la Recherche Médicale U450, Association Claude Bernard, 75270 Paris cedex 06, France, and 2 Augenklinik der Charité, Virchow-Klinikum, Humboldt Universität, 13353 Berlin, Germany
Ischemic proliferative retinopathy (e.g., diabetes mellitus, retinopathy of prematurity, or retinal vein occlusion) is a major cause of blindness worldwide. Apart from neovascularization, ischemic proliferative retinopathy leads to retinal degeneration. Apoptosis has been ascribed to be the leading mechanism in ischemic retinal degeneration. We showed recently that inducible nitric oxide synthase (iNOS) is expressed in the avascular retina in proliferative retinopathy in vivo and that iNOS expression in retinal glial cells is responsible for retinal neuronal cell death in vitro. Here we show that retinal apoptosis and subsequent degeneration occur in the murine model of ischemic proliferative retinopathy. Furthermore, because NO can have beneficial or detrimental effects in the retina, we analyzed the role of iNOS on retinal apoptosis in ischemic proliferative retinopathy. Using iNOS knock-out mice and iNOS inhibitor 1400W, we demonstrate in vivo that iNOS expression induces apoptosis locally in the inner nuclear layer of the avascular retina and that protein nitration may be involved in this process.
These findings are the first evidence for retinal apoptosis in an animal model of ischemic proliferative retinopathy, demonstrating that iNOS plays a crucial role not only in retinal neovascular disease but also in retinal degeneration. We show that it is an ideal target to protect the hypoxic retina from degeneration and to improve its vascularization.
Key words: inducible nitric oxide synthase; apoptosis; retina; knock-out mice; ROP; ischemia; peroxynitrite; neovascularization
Copyright © 2002 Society for Neuroscience 0270-6474/02/22103987-07$05.00/0
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