RT Journal Article
SR Electronic
T1 Early Intervention of Tyrosine Nitration Prevents Vaso-obliteration and Neovascularization in Ischemic Retinopathy
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.109.157941
DO 10.1124/jpet.109.157941
A1 Abdelsaid, Moahmmed A.
A1 Pillai, Bindu A.
A1 Matragoon, Suraporn
A1 Prakash, Roshini
A1 Al-Shabrawey, Mohamed
A1 El-Remessy, Azza B.
YR 2009
UL http://jpet.aspetjournals.org/content/early/2009/10/08/jpet.109.157941.abstract
AB Diabetic retinopathy and retinopathy of prematurity are blinding disorders that follow a pathological pattern of ischemic retinopathy and affect premature infants and working age adults. Yet, the treatment options are limited to laser-photocoagulation. The goal of this study is to elucidate the molecular mechanism and examine the therapeutic effects of inhibiting tyrosine nitration on protecting early retinal vascular cell death and late neovascularization in ischemic retinopathy model. Ischemic retinopathy was developed by exposing neonatal mice to 75% oxygen (p7-p12) followed by normoxia 21% oxygen (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). Vascular 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-induced peroxynitrite caused endothelial cell apoptosis as indicated by expression of cleaved caspase-3 and PARP leading to vaso-obliteration. These effects were associated with significant tyrosine nitration of the p85-subunit of PI-3kinase, decreased Akt activation and enhanced p38 MAPK activation. Blocking tyrosine nitration of PI-3kinase with epicatechin or NAC restored Akt phosphorylation, and inhibited vaso-obliteration at p12 and neovascularization at p17 comparable to FeTPPs. Early inhibition of tyrosine nitration using epicatechin or NAC can represent safe and effective vascular protective agents in ischemic retinopathy.The American Society for Pharmacology and Experimental Therapeutics