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Research ArticleCELLULAR AND MOLECULAR

Early Intervention of Tyrosine Nitration Prevents Vaso-Obliteration and Neovascularization in Ischemic Retinopathy

Mohammed A. Abdelsaid, Bindu A. Pillai, Suraporn Matragoon, Roshini Prakash, Mohamed Al-Shabrawey and Azza B. El-Remessy
Journal of Pharmacology and Experimental Therapeutics January 2010, 332 (1) 125-134; DOI: https://doi.org/10.1124/jpet.109.157941
Mohammed A. Abdelsaid
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Bindu A. Pillai
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Suraporn Matragoon
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Roshini Prakash
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Mohamed Al-Shabrawey
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Azza B. El-Remessy
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Abstract

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 the ischemic retinopathy model. Ischemic retinopathy was developed by exposing neonatal mice to 75% oxygen [postnatal day (p) 7–p12] followed by normoxia (21% oxygen) (p12–p17). Peroxynitrite decomposition catalyst 5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride (FeTPPS) (1 mg/kg), the nitration inhibitor epicatechin (10 mg/kg) or the thiol donor N-acetylcysteine (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 h. Vascular density was determined in retinal flat mounts labeled with isolectin B4. Expression of vascular endothelial growth factor, caspase-3, and poly(ADP ribose) polymerase (PARP), activation of Akt and p38 mitogen-activated protein kinase (MAPK), and tyrosine nitration of the phosphatidylinositol (PI) 3-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 3-kinase, decreased Akt activation, and enhanced p38 MAPK activation. Blocking tyrosine nitration of PI 3-kinase with epicatechin or NAC restored Akt phosphorylation, and inhibited vaso-obliteration at p12 and neovascularization at p17 comparable with FeTPPS. Early inhibition of tyrosine nitration with use of epicatechin or NAC can represent safe and effective vascular-protective agents in ischemic retinopathy.

Footnotes

  • This work was supported by the American Heart Association [Scientist Development Grant 0530170N] (to A.B.E.); the Juvenile Diabetes Research Foundation [Grant 1-2008-49] (to A.B.E.); and the University of Georgia Research Foundation (A.B.E.).

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.157941

  • ABBREVIATIONS:

    ROP
    retinopathy of prematurity
    DR
    diabetic retinopathy
    BRE
    bovine retinal endothelial
    VEGF
    vascular endothelial growth factor
    FeTPPS
    5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato iron III chloride
    PARP
    poly(ADP ribose) polymerase
    p
    postnatal day
    PI
    phosphatidylinositol
    NAC
    N-acetylcysteine
    PBS
    phosphate-buffered saline
    MAPK
    mitogen-activated protein kinase
    GSH
    reduced glutathione
    GSSG
    oxidized glutathione.

    • Received June 19, 2009.
    • Accepted October 8, 2009.
  • © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 332 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 332, Issue 1
1 Jan 2010
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Research ArticleCELLULAR AND MOLECULAR

Early Intervention of Tyrosine Nitration Prevents Vaso-Obliteration and Neovascularization in Ischemic Retinopathy

Mohammed A. Abdelsaid, Bindu A. Pillai, Suraporn Matragoon, Roshini Prakash, Mohamed Al-Shabrawey and Azza B. El-Remessy
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 125-134; DOI: https://doi.org/10.1124/jpet.109.157941

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Research ArticleCELLULAR AND MOLECULAR

Early Intervention of Tyrosine Nitration Prevents Vaso-Obliteration and Neovascularization in Ischemic Retinopathy

Mohammed A. Abdelsaid, Bindu A. Pillai, Suraporn Matragoon, Roshini Prakash, Mohamed Al-Shabrawey and Azza B. El-Remessy
Journal of Pharmacology and Experimental Therapeutics January 1, 2010, 332 (1) 125-134; DOI: https://doi.org/10.1124/jpet.109.157941
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