Circulation Research. 2001;89:13-19
Published online before print June 21, 2001, doi: 10.1161/hh1301.092506
Published online before print June 21, 2001, doi: 10.1161/hh1301.092506
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© 2001 American Heart Association, Inc.
Molecular Medicine |
Phosphatidylinositol 3-Kinase/Akt Signaling Controls Endothelial Cell Sensitivity to Fas-Mediated Apoptosis via Regulation of FLICE-Inhibitory Protein (FLIP)
From the Division of Cardiovascular Research (T.S., T.M., K.W.), St. Elizabeth’s Medical Center, and the Program in Cell, Molecular, and Developmental Biology (B.E.O., K.W.), Department of Anatomy and Cellular Biology, Tufts University School of Medicine, Boston, Mass, and The First Department of Medicine (T.M.), Osaka University School of Medicine, Suita, Osaka, Japan.
Correspondence to Kenneth Walsh, PhD, Division of Cardiovascular Research, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail kwalsh@world.std.com and kwalsh{at}opal.tufts.edu
Abstract
Abstract—Fas is constitutively expressed on endothelial cells, but in contrast to smooth muscle and other cell types, endothelial cells are highly resistant to Fas-mediated apoptosis. In this study, we examined the role of the serine/threonine kinase Akt/PKB in controlling the sensitivity of endothelial cells to Fas-mediated apoptosis. Serum deprivation inhibited expression of the caspase-8 inhibitor FLICE-inhibitory protein (FLIP), which functions downstream from Fas. FLIP expression levels were restored when serum-depleted cells were treated with vascular endothelial growth factor. Treatment with the phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors wortmannin or LY294002 or infection of the adenoviral construct expressing dominant-negative Akt (Adeno-dnAkt) also inhibited the expression of FLIP in endothelial cells, whereas the MEK inhibitor PD98059 had no effect. Conversely, adenovirus-mediated transfection of a constitutively-active Akt gene abolished the wortmannin- and LY294002-mediated downregulation of FLIP. Suppression of PI 3-kinase signaling sensitized endothelial cells to Fas-mediated apoptosis. Under conditions of suppressed PI 3-kinase signaling, restoration of FLIP expression reversed the induced sensitivity of endothelial cells to Fas-mediated apoptosis. These data suggest that inhibition of Fas-mediated apoptosis, via promotion of FLIP expression, is a mechanism through which Akt signaling can promote endothelial cell survival.
Key Words: apoptosis • cell signaling • signal transduction • growth factors • cytokines
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