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Molecular and Cellular Biology, June 2005, p. 4742-4751, Vol. 25, No. 11
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.11.4742-4751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

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, and Augustine M. K. Choi*

Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania 15213

Received 30 October 2004/ Returned for modification 13 December 2004/ Accepted 28 February 2005

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) ({alpha}, {zeta}) 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.

* Corresponding author. Mailing address: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Pittsburgh Medical Center, 3459 Fifth Ave., MUH NW 628, Pittsburgh, PA 15213. Phone: (412) 692-2210. Fax: (412) 692-2260. E-mail: choiam{at}msx.upmc.edu.

Molecular and Cellular Biology, June 2005, p. 4742-4751, Vol. 25, No. 11
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.11.4742-4751.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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