FLIP inhibits endothelial cell apoptosis during hyperoxia by suppressing Bax

Xue Wang, Yong Wang, Hong Pyo Kim, Augustine M.K. Choi, Stefan W. Ryter

Research output: Contribution to journalArticlepeer-review

21 Scopus citations


High oxygen tension (hyperoxia) causes pulmonary cell death, involving apoptosis, necrosis, or mixed death phenotypes, though the underlying mechanisms remain unclear. In mouse lung endothelial cells (MLEC) hyperoxia activates both extrinsic (Fas-dependent) and intrinsic (mitochondria-dependent) apoptotic pathways. We examined the hypothesis that FLIP, an inhibitor of caspase-8, can protect endothelial cells against the lethal effects of hyperoxia. Hyperoxia caused the time-dependent downregulation of FLIP in MLEC. Overexpression of FLIP attenuated intracellular reactive oxygen species generation during hyperoxia exposure, by downregulating extracellular-regulated kinase-1/2 activation and p47phox expression. FLIP prevented hyperoxia-induced trafficking of the death-inducing signal complex from the Golgi apparatus to the plasma membrane. Furthermore, FLIP blocked the activations of caspase-8/Bid, caspases -3/-9, and inhibited the mitochondrial translocation and activation of Bax, resulting in protection against hyperoxia-induced cell death. Under normoxic conditions, FLIP expression increased the phosphorylation of p38 mitogen-activated protein kinase leading to increased phosphorylation of Bax during hyperoxic stress. Furthermore, FLIP expression markedly inhibited protein kinase C activation and expression of distinct protein kinase C isoforms (α, η, and ζ), and stabilized an interaction of PKC with Bax. In conclusion, FLIP exerted novel inhibitory effects on extrinsic and intrinsic apoptotic pathways, which significantly protected endothelial cells from the lethal effects of hyperoxia.

Original languageEnglish (US)
Pages (from-to)1599-1609
Number of pages11
JournalFree Radical Biology and Medicine
Issue number10
StatePublished - May 15 2007


  • Apoptosis
  • Bax
  • FLIP
  • Hyperoxia
  • Protein kinase C

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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