W. Erl et al., Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells, CIRCUL RES, 84(6), 1999, pp. 668-677
Apoptosis is important in normal development as well as in diseases such as
atherosclerosis. However, the regulation of apoptosis is still not complet
ely understood. We now show that the transcription factor nuclear factor-ka
ppa B (NF-kappa B) controls the induction of apoptosis in human and rat vas
cular smooth muscle cells (SMCs). SMCs in high-density culture exhibited a
high NF-kappa B activity and were insensitive to induction of apoptosis. In
hibition of NF-kappa B by adenovirus-mediated overexpression of its inhibit
or I kappa B alpha caused a marked increase in cell death at low but not hi
gh cell density. Elevating endogenous I kappa B alpha levels by inhibiting
its degradation with proteasomal inhibitors resulted in induction of apopto
sis in low-density SMCs, as detected by increased binding of annexin V, red
uced mitochondrial membrane potential, and increased hypodiploid DNA. In hi
gh-density cultures, protection against apoptosis was associated with the e
xpression of inhibitor of apnptosis protein-1 (IAP-1). Transfer of I kappa
B alpha reduced human IAP-1 mRNA levels, which suggested that IAP-1 is tran
scriptionally regulated by NF-kappa B. This was confirmed through identific
ation of a motif with NF-kappa B-like binding activity in the human IAP-1 p
romoter region. Moreover, antisense inhibition of IAP-1 sensitized high-den
sity SMCs to the induction of cell death. Together, our data imply that SMC
s at high density are protected by an antiapoptotic mechanism that involves
increased expression of NF-kappa B and IAP-1. Interference with pathways t
hat control the susceptibility to programmed cell death may be helpful in t
he treatment of diseases where dysregulation of apoptosis is involved, eg,
atherosclerosis and restenosis.