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

Xue Wang1, Yong Wang, Jinglan Zhang

  • 1Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, 3459 Fifth Ave., MUH NW 628, Pittsburgh, PA 15213, USA.

Molecular and Cellular Biology
|May 19, 2005
PubMed

Insights

FLIP protects mouse lung endothelial cells from hypoxia/reoxygenation injury by inhibiting both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. This protection involves novel mechanisms including protein kinase C inhibition and altered death-inducing signal complex localization.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Hypoxia/reoxygenation induces cell death through poorly understood mechanisms.
  • Apoptotic pathways, including death receptor and mitochondrial routes involving Bid and Bax, are activated.
  • FLIP (FLICE-inhibitory protein) is known to inhibit caspase 8.

Purpose of the Study:

  • To investigate the role of FLIP in hypoxia/reoxygenation-induced cell death in mouse lung endothelial cells (MLEC).
  • To elucidate the specific apoptotic pathways regulated by FLIP during cellular stress.

Main Methods:

  • Utilized mouse lung endothelial cells (MLEC) subjected to hypoxia/reoxygenation.
  • Assessed the impact of FLIP expression on caspase 8/Bid and Bax/mitochondrial apoptotic pathways.
  • Examined protein kinase C (PKC) activation, Bax activation, and death-inducing signal complex (DISC) formation.
  • Investigated the expression of antiapoptotic protein Bcl-X(L).

Main Results:

  • FLIP protected MLEC against hypoxia/reoxygenation-induced cell death.
  • FLIP inhibited both caspase 8/Bid and Bax/mitochondrial apoptotic pathways, independent of Bid.
  • FLIP suppressed protein kinase C (PKC) (alpha, zeta) expression and activation, associating inactive PKC with Bax.
  • FLIP reduced plasma membrane DISC formation, promoting its accumulation in the Golgi apparatus, and upregulated Bcl-X(L).

Conclusions:

  • FLIP confers protection against hypoxia/reoxygenation injury in endothelial cells.
  • FLIP inhibits Bax activation via a novel PKC-dependent mechanism and by reducing plasma membrane DISC formation.
  • FLIP's effects on DISC translocation and Bax activation are key to protecting endothelial cells during hypoxia/reoxygenation stress.

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