FLIP protects against hypoxia/reoxygenation-induced endothelial cell apoptosis by inhibiting bax activation

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

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Hypoxia/reoxygenation causes cell death, yet the underlying regulatory mechanisms remain partially understood. Recent studies demonstrate that hypoxia/reoxygenation can activate death receptor and mitochondria-dependent apoptotic pathways, involving Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of FLIP, an inhibitor of caspase 8, in hypoxia/reoxygenation-induced cell death. FLIP protected MLEC against hypoxia/reoxygenation by blocking both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. FLIP inhibited Bax activation in wild-type and Bid-/- MLEC, indicating independence from the caspase 8/Bid pathway. FLIP also inhibited the expression and activation of protein kinase C (PKC) (α, ζ) during hypoxia/reoxygenation and promoted an association of inactive forms of PKC with Bax. Surprisingly, FLIP expression also inhibited death-inducing signal complex (DISC) formation in the plasma membrane and promoted the accumulation of the DISC in the Golgi apparatus. FLIP expression also upregulated Bcl-XL, an antiapoptotic protein. In conclusion, FLIP decreased DISC formation in the plasma membrane by blocking its translocation from the Golgi apparatus and inhibited Bax activation through a novel PKC-dependent mechanism. The inhibitory effects of FLIP on Bax activation and plasma membrane DISC formation may play significant roles in protecting endothelial cells from the lethal effects of hypoxia/reoxygenation.

Original languageEnglish (US)
Pages (from-to)4742-4751
Number of pages10
JournalMolecular and Cellular Biology
Volume25
Issue number11
DOIs
StatePublished - Jun 2005

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'FLIP protects against hypoxia/reoxygenation-induced endothelial cell apoptosis by inhibiting bax activation'. Together they form a unique fingerprint.

Cite this