Antioxidant status alters levels of fas-associated death domain-like IL-1B-converting enzyme inhibitory protein following neonatal hypoxia-ischemia

Kurlen S.E. Payton, R. Ann Sheldon, Devin W. Mack, Chainglian Zhu, Klas Blomgren, Donna M. Ferriero, Frances J. Northington

Research output: Contribution to journalArticlepeer-review

Abstract

Activation of Fas death receptor (Fas DR) signaling cascade is seen after neonatal hypoxia-ischemia (HI). Cell survival is favored when signaling through the death-inducing signaling complex and cleavage of caspase 8 to its active form is blocked by FLIP, a dominant negative of caspase 8. H2O 2 quickly downregulates expression of FLIP. Neonatal mice overexpressing glutathione peroxidase (GPx) have less injury and less H 2O2 accumulation compared with neonatal mice overexpressing superoxide dismutase (SOD) or wild-type (WT) littermates. Expression of both FLIPL and FLIPS is increased in GPx-oxerexpressing mice relative to WT mice at 24 h and relative to SOD-overexpressing mice at 2 and 24 h following neonatal HI (ANOVA, p < 0.05). There is an increase in Fas DR expression at 24 h in both WT and GPx-overexpressing mice and significant differences between WT and SOD-overexpressing mice (ANOVA, p < 0.01). There is no difference in FADD expression among the 3 groups 24 h after HI. At 24 h following HI, the ratio of FLIP to Fas DR expression supports a significant negative correlation with injury score (r2 = 0.99, slope = -4.01), and expression of both the active fragment of caspase 8 and caspase 8 activity is increased in SOD overexpressors compared to GPx overexpressors at 24 h after HI (ANOVA, p < 0.05). The overall degree of injury previously seen in these 3 strains correlates well with changes in expression of Fas DR signaling proteins favoring neuroprotection in the GPx-overexpressing mice, i.e. increased FLIP expression and decreased caspase 8 activity compared to SODtg mice. The mechanism by which antioxidant status alters FLIP levels following neonatal HI may be related to the ability to detoxify H2O2 produced following neonatal HI.

Original languageEnglish (US)
Pages (from-to)403-411
Number of pages9
JournalDevelopmental Neuroscience
Volume29
Issue number4-5
DOIs
StatePublished - Aug 2007

Keywords

  • Fas death receptor signaling
  • Fas-associated death domain-like IL-1β-converting enzyme inhibitory protein
  • Glutathione peroxidase
  • Hypoxia-ischemia
  • Neonatal brain injury
  • Superoxide dismutase

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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