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Dual role of peroxynitrite in oxygen‐induced retinopathy: oxidation versus nitration
Author(s) -
ElRemessy Azza B.,
AlShabrawey Mohamed,
Bartoli Manuela,
Miller Telina,
Caldwell Robert W.,
Caldwell Ruth B.
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1084-a
Subject(s) - peroxynitrite , chemistry , tyrosine phosphorylation , neovascularization , phosphorylation , protein kinase b , nitration , retinal , microbiology and biotechnology , tyrosine , biochemistry , cancer research , angiogenesis , superoxide , biology , organic chemistry , enzyme
We have shown that high levels of peroxynitrite (0.5 mM) inactivate VEGF survival signaling and accelerate endothelial cell death by inhibiting Akt kinase via tyrosine nitration of PI3‐kinase's p85 subunit. We have also shown that low levels of peroxynitrite (1μM) mimic the effects of VEGF in causing tyrosine phosphorylation of VEGFR2, c‐Src and FAK. These data suggest a dual role of peroxynitrite in altering VEGF‐mediated survival and growth signals. Here, we compare the effects of blocking peroxynitrite formation with FETTPs (1mg/Kg/day) or nitration with epicatechin (10mg/Kg/day) on hyperoxia‐induced vaso‐obliteration and hypoxia‐induced neovascularization. Neonatal mice were exposed to 75% oxygen from P7 to P12, which caused retinal vaso‐obliteration, decreased Akt activation, increased tyrosine nitration of PI3‐kinase and lipid peroxidation. Treatments from P7–P12 with FeTTPs or epicatechin restored Akt phosphorylation, blocked tyrosine nitration and prevented capillary cell death. Hypoxia‐induced neovascularization was achieved by exposing mice to 75% oxygen as before followed by 5 days in room air (hypoxic period). This resulted in significant retinal neovascularization, which was blocked by FeTTPs but not epicatechin. Taken together, these results demonstrate that peroxynitrite, a powerful oxidizing and nitrating agent plays a critical role in mediating both growth and death of the microvasculature. Our finding that inhibiting nitration blocks vaso‐obliteration, but not neovascularization indicates that the death signal involves peroxynitrite‐mediated nitration, whereas the angiogenic signal does not, but may instead depend on peroxynitrite‐mediated oxidation.