© 2000 American Heart Association, Inc.
Vascular Biology |
Insulin-Mediated Stimulation of Protein Kinase Akt
A Potent Survival Signaling Cascade for Endothelial Cells
From Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.
Correspondence to Stefanie Dimmeler, PhD, Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. E-mail Dimmeler{at}em.uni-frankfurt.de
Abstract—Insulin exerts potent
antiapoptotic effects in neuronal cells and has been suggested
to promote angiogenesis. Therefore, we investigated whether insulin
inhibits tumor necrosis factor-
(TNF-)–induced apoptosis
in human umbilical vein endothelial cells (HUVECs).
Because insulin has been shown to stimulate the protein kinase Akt, we
investigated whether activation of Akt contributes to the
apoptosis-suppressive effect of insulin and characterized the
downstream signaling pathway. Incubation with insulin dose-dependently
prevented apoptosis induced by TNF- (50 ng/mL). The extent
of apoptosis suppression by insulin was similar to the effect
of vascular endothelial growth factor. Pharmacological
inhibition of Akt activation or overexpression of a dominant-negative
Akt mutant prevented the antiapoptotic effect of insulin.
Furthermore, we investigated the effect of TNF- on Akt
phosphorylation by Western blot analysis with
the use of a phosphospecific Akt antibody. Incubation of HUVECs with
TNF- induced a marked dephosphorylation of Akt.
Insulin counteracted this TNF-–induced
dephosphorylation of Akt. Furthermore, we investigated
the downstream signaling events. Akt has been shown to mediate its
apoptosis-suppressive effects via
phosphorylation of Bad or caspase-9. However,
incubation with insulin did not lead to enhanced
phosphorylation of Bad at Ser 136 or Ser 112. In
contrast, insulin inhibited caspase-9 activity and prevented
caspase-9–induced apoptosis. Mutation of the Akt site within
caspase-9 significantly reduced the apoptosis-suppressive
effect of insulin. The present study demonstrates an
important role for insulin-mediated Akt activation in the prevention of
endothelial cell apoptosis, which may
importantly contribute to cell homeostasis and the integrity of the
endothelium. In endothelial cells, Akt
seems to mediate its antiapoptotic effect, at least in part,
via phosphorylation of caspase-9 rather than Bad.
Key Words: endothelial cells • insulin • Akt kinase • atherosclerosis
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