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American Journal of Pathology, Vol 151, 1775-1784, Copyright © 1997 by American Society for Investigative Pathology
REGULAR ARTICLES |
A Karsan, E Yee, GG Poirier, P Zhou, R Craig and JM Harlan
McDonald Research Laboratories, University of British Columbia, Vancouver, Canada.
Intact endothelium acts as a sensor and transducer of signals and also provides a nonthrombogenic surface at the blood-vascular wall interface. Hence, mechanisms that maintain the integrity of the endothelium are of interest in physiological and pathological states. In this study we show that apoptosis induced by growth factor and serum deprivation of endothelial cells occurs at all phases of the cell cycle and can be blocked by fibroblast growth factor-2 (FGF-2) independently of its mitogenic activity. As the Bcl-2 family of proteins plays a prominent role in regulating cell survival, we attempted to identify Bcl-2 homologues expressed in endothelial cells. Here we demonstrate that, in addition to the previously identified A1, four other members of the Bcl-2 family, Bcl-2, Mcl-1, Bcl-X(L), and Bax, are expressed in endothelial cells. Of these family members, only Bcl-2 is induced by FGF-2. Overexpression of Bcl-2, using a retroviral vector, protects endothelial cells from serum and growth factor deprivation. There is no difference in FGF-2-induced proliferation between Bcl-2-overexpressing cells and those transduced with the empty retroviral vector. At early time points Bcl-2 is not up-regulated, but FGF-2 still has a protective effect. However, FGF-2 protects only adherent endothelial cells but not those that are cultured in suspension. The early effect of FGF-2 is dependent on tyrosine phosphorylation but not on activation of the MAP kinase pathway. Thus, FGF-2 inhibits endothelial cell apoptosis by Bcl- 2-dependent and independent mechanisms.
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K. E. Noble, R. G. Wickremasinghe, C. DeCornet, P. Panayiotidis, and K. L. Yong Monocytes Stimulate Expression of the Bcl-2 Family Member, A1, in Endothelial Cells and Confer Protection Against Apoptosis J. Immunol., February 1, 1999; 162(3): 1376 - 1383. [Abstract] [Full Text] [PDF]
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X. Hu, E. Yee, J. M. Harlan, F. Wong, and A. Karsan Lipopolysaccharide Induces the Antiapoptotic Molecules, A1 and A20, in Microvascular Endothelial Cells Blood, October 15, 1998; 92(8): 2759 - 2765. [Abstract] [Full Text] [PDF]
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K.-B. Choi, F. Wong, J. M. Harlan, P. M. Chaudhary, L. Hood, and A. Karsan Lipopolysaccharide Mediates Endothelial Apoptosis by a FADD-dependent Pathway J. Biol. Chem., August 7, 1998; 273(32): 20185 - 20188. [Abstract] [Full Text] [PDF]
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D. D. Bannerman, J. C. Tupper, W. A. Ricketts, C. F. Bennett, R. K. Winn, and J. M. Harlan A Constitutive Cytoprotective Pathway Protects Endothelial Cells from Lipopolysaccharide-induced Apoptosis J. Biol. Chem., April 27, 2001; 276(18): 14924 - 14932. [Abstract] [Full Text] [PDF]
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P. J. Duriez, F. Wong, K. Dorovini-Zis, R. Shahidi, and A. Karsan A1 Functions at the Mitochondria to Delay Endothelial Apoptosis in Response to Tumor Necrosis Factor J. Biol. Chem., June 9, 2000; 275(24): 18099 - 18107. [Abstract] [Full Text] [PDF]
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