TRAIL-Induced Apoptosis in Human Vascular Endothelium Is Regulated by Phosphatidylinositol 3-Kinase/Akt through the Short Form of Cellular FLIP and Bcl-2

Vol. 42, No. 4, 2005

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Research Paper

TRAIL-Induced Apoptosis in Human Vascular Endothelium Is Regulated by Phosphatidylinositol 3-Kinase/Akt through the Short Form of Cellular FLIP and Bcl-2
Salima J. Alladina^a, Jin H. Song^a, Sandra T. Davidge^{b, c}, Chunhai Hao^a, Alexander S. Easton^{a, b}

Departments of
^aLaboratory Medicine and Pathology,
^bPhysiology and
^cObstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada

Address of Corresponding Author

J Vasc Res 2005;42:337-347 (DOI: 10.1159/000086599)

Key Words

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)
Apoptosis
Endothelium

Abstract

Background: Apoptosis of vascular endothelial cells plays a central role in angiogenesis and atherosclerosis. This study investigates the molecular mechanisms of endothelial apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) following inhibition of phosphatidylinositol 3-kinase (PI3K). It examines downstream regulation and activation of the extrinsic and intrinsic pathways. Methods and Results: By flow cytometry, TRAIL receptors 2 and 3 were present to a greater extent than receptors 1 and 4. TRAIL reduced cell numbers in combination with the PI3K inhibitor LY 294002. TRAIL (100 ng/ml) with LY 294002 (20 µmol/l) activated the extrinsic pathway, causing progressive cleavage of caspase-8 and caspase-3. Activation of the intrinsic pathway proceeded by release of mitochondrial factors Smac/DIABLO and cytochrome c, and caspase-9 cleavage. LY 294002 reduced phosphorylated Akt (p-Akt), with early loss of the short form of cellular FLIP (c-FLIP_S) and concurrent reduction of Bcl-2. Treatment with small interfering RNA against PI3K also reduced c-FLIP_S and Bcl-2, and cotreatment with TRAIL triggered caspase-3 cleavage. Conclusions: This study details the molecular regulation of TRAIL-induced apoptosis in vascular endothelium. Inhibition of PI3K reduces p-Akt, with concurrent reductions in c-FLIP_S and Bcl-2, and so renders endothelium sensitive to TRAIL-induced apoptosis through the extrinsic and intrinsic pathways.

Author Contacts

Dr. Alexander S. Easton
Department of Pathology, Dalhousie University
11J1 Sir Charles Tupper Medical Building, 5859 University Avenue
Halifax, Nova Scotia B3H 4H7 (Canada)
Tel. +1 902 494 6651, Fax +1 902 494 2519, E-Mail Alexander.Easton@dal.ca

Article Information

Received: December 17, 2004
Accepted after revision: May 17, 2005
Published online: June 28, 2005
Number of Print Pages : 11
Number of Figures : 5, Number of Tables : 0, Number of References : 69

Medline Abstract (ID 15985761)

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