Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite

Xiaolin Gu, Azza B. El-Remessy, Steven E. Brooks, Mohamed Al-Shabrawey, Nai Tsi Tsai, Ruth B Caldwell

Research output: Contribution to journalArticle

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Abstract

Hyperoxia exposure induces capillary endothelial cell apoptosis in the developing retina, leading to vaso-obliteration followed by proliferative retinopathy. Previous in vivo studies have shown that endothelial nitric oxide synthase (NOS3) and peroxynitrite are important mediators of the vaso-obliteration. Now we have investigated the relationship between hyperoxia, NOS3, peroxynitrite, and endothelial cell apoptosis by in vitro experiments using bovine retinal endothelial cells (BREC). We found that BREC exposed to 40% oxygen (hyperoxia) for 48 h underwent apoptosis associated with activation of caspase-3 and cleavage of the caspase substrate poly(ADP-ribose) polymerase. Hyperoxia-induced apoptosis was associated with increased formation of nitric oxide, peroxynitrite, and superoxide anion and was blocked by treatment with uric acid, nitro-L-arginine methyl ester, or superoxide dismutase. Analyses of the phosphatidylinositol 3-kinase/Akt kinase survival pathway in cells directly treated with peroxynitrite revealed inhibition of VEGF- and basic FGF-induced activation of Akt kinase. These results suggest that hyperoxia-induced formation of peroxynitrite induces BREC apoptosis by crippling key survival pathways and that blocking peroxynitrite formation prevents apoptosis. These data may have important clinical implications for infants at risk of retinopathy of prematurity.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Cell Physiology
Volume285
Issue number3 54-3
StatePublished - Sep 1 2003

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Retinal Vessels
Hyperoxia
Peroxynitrous Acid
Endothelial Cells
Apoptosis
Phosphotransferases
Phosphatidylinositol 3-Kinase
Retinopathy of Prematurity
Poly(ADP-ribose) Polymerases
Nitric Oxide Synthase Type III
Caspases
Uric Acid
Superoxides
Caspase 3
Vascular Endothelial Growth Factor A
Superoxide Dismutase
Retina
Nitric Oxide
Oxygen

Keywords

  • Nitric oxide
  • Oxygen-induced retinopathy
  • Superoxide
  • Vaso-obliteration

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

Cite this

Hyperoxia induces retinal vascular endothelial cell apoptosis through formation of peroxynitrite. / Gu, Xiaolin; El-Remessy, Azza B.; Brooks, Steven E.; Al-Shabrawey, Mohamed; Tsai, Nai Tsi; Caldwell, Ruth B.

In: American Journal of Physiology - Cell Physiology, Vol. 285, No. 3 54-3, 01.09.2003.

Research output: Contribution to journalArticle

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