© 1999 American Heart Association, Inc.
Original Contribution |
Regulation of Vascular Smooth Muscle Cell Apoptosis
Modulation of Bad by a Phosphatidylinositol 3-Kinase–Dependent Pathway
From the Molecular Vascular Cell Biology Research Laboratory, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St, Boston, Mass.
Correspondence to Gary H. Gibbons, MD, Cardiovascular Research Institute, Morehouse School of Medicine, 720 Westview Dr SW, Atlanta, GA 30310-1495.
Abstract—Our objective was to
define the signaling mechanisms by which mitogens such as insulin-like
growth factor-I (IGF-I) regulate vascular smooth muscle cell (VSMC)
apoptosis. We confirmed that IGF-I inhibits serum
withdrawal–induced apoptosis of cultured VSMCs in a
dose-dependent and time-dependent fashion. To test the hypothesis that
the phosphatidylinositol (PI) 3-kinase signaling pathway regulates VSMC
survival, we examined the relationship between PI 3-kinase activity and
cell fate. PI 3-kinase was elevated in viable VSMCs maintained in
serum-containing medium, declined significantly in response to serum
withdrawal, and increased in response to IGF-I–induced survival.
Moreover, blockade of PI 3-kinase with 2 structurally dissimilar
inhibitors (wortmannin or LY294002) abolished the capacity
of IGF-I to maintain VSMC viability. Similarly, transient transfection
of a dominant-negative 
p85 PI 3-kinase mutant construct abrogated
the capacity of IGF-I to prevent VSMC death. Thus, PI 3-kinase is a
critical antiapoptotic signal in VSMCs. To define the distal
element of the antiapoptotic cascade, we tested the hypothesis
that IGF-I inhibits the influence of the proapoptotic gene Bad.
Indeed, IGF-I stimulates increased expression of the inactive,
phosphorylated form of Bad by a PI 3-kinase–dependent
pathway. Moreover, the proapoptotic effect of Bad was
attenuated by the stimulation of IGF-I. Thus, growth factors appear to
prevent VSMC death by activating signal transduction pathways linked to
apoptotic regulatory genes.
Key Words: vascular smooth muscle cell • insulin-like growth factor-I • phosphatidylinositol 3-kinase • programmed cell death • Bad
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