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M. A. Abdelsaid, B. A. Pillai, S. Matragoon, R. Prakash, M. Al-shabrawey, A. B. El-Remessy; Early Intervention of Tyrosine Nitration Prevents Vaso-Obliteration and Neovascularization in Ischemic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2009;50(13):5357.
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We have shown that while peroxynitrite can block VEGF’ survival signal and promote endothelial cell death via tyrosine nitration, it can mediate VEGF’ angiogenic signal via tyrosine nitration-independent mechanism. The goal of this study is to elucidate the role of peroxynitrite and tyrosine nitration in mediating early retinal cell death and vaso-obliteration and late neovascularization in ischemic retinopathy model.
Oxygen-induced retinopathy was developed by exposing neonatal mice to 75% oxygen (p7-p12) followed by normoxia (p12-p17). Peroxynitrite decomposition catalyst FeTPPs (1 mg/Kg), the nitration inhibitor epicatechin (10 mg/Kg) or the thiol donor N-acetyl cysteine (NAC, 150 mg/Kg) were administered (P7-P12) or (p7-p17). Retinal endothelial cells were incubated at hyperoxia (40% oxygen) or normoxia (21% oxygen) for 48 hours. Vascular density was determined in retinal flat-mounts labeled with iso-lectin B4. Expression of VEGF, caspase-3 and PARP, Activation of Akt and p38 MAPK and tyrosine nitration of the PI3 kinase p85 subunit were analyzed by Western-blot.
Hyperoxia caused vaso-obliteration in vivo and retinal endothelial apoptosis in vitro and increased expression of cleaved caspase-3 and PARP. These effects were associated with significant tyrosine nitration of the p85 subunit of PI-3kinase, decreased Akt activation and enhanced p38 MAPK activation. Treatment with epicatechin blocked tyrosine nitration of PI-3kinase, restored Akt phosphorylation, and inhibited vaso-obliteration at p12 and neovascularization at p17 comparable to FeTPPs and NAC.
Peroxynitrite and tyrosine nitration play a critical role in mediating retinal cell death and vaso-obliteration. Early inhibition of tyrosine nitration can protect the retina from ischemic retinopathy.
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