© 1999 American Heart Association, Inc.
Original Contribution |
Nuclear Factor-
B Regulates Induction of Apoptosis and Inhibitor of Apoptosis Protein-1 Expression in Vascular Smooth Muscle Cells
From the Cardiovascular Research Unit, Center for Molecular Medicine (W.E., G.K.H.), Karolinska Institute, Stockholm, Sweden; the Vienna International Research Cooperation Center (R.d.M.), Wien, Austria; and the Institut für Prophylaxe der Kreislaufkrankheiten (G.D., K.S.C.W., C.W.), München, Germany.
Correspondence to Dr Wolfgang Erl, Cardiovascular Research Unit, CMM L8:03, Karolinska Hospital, S-17176 Stockholm, Sweden. E-mail wolfgang.erl{at}cmm.ki.se
Abstract—Apoptosis
is important in normal development as well as in diseases such as
atherosclerosis. However, the regulation of
apoptosis is still not completely understood. We now show that
the transcription factor nuclear factor-
B (NF-B) controls the
induction of apoptosis in human and rat vascular smooth muscle
cells (SMCs). SMCs in high-density culture exhibited a high NF-B
activity and were insensitive to induction of apoptosis.
Inhibition of NF-B by adenovirus-mediated overexpression of its
inhibitor IB
caused a marked increase in cell death
at low but not high cell density. Elevating endogenous
IB levels by inhibiting its degradation with proteasomal
inhibitors resulted in induction of apoptosis in
low-density SMCs, as detected by increased binding of annexin V,
reduced mitochondrial membrane potential, and increased hypodiploid
DNA. In high-density cultures, protection against apoptosis was
associated with the expression of inhibitor of
apoptosis protein-1 (IAP-1). Transfer of IB reduced human
IAP-1 mRNA levels, which suggested that IAP-1 is transcriptionally
regulated by NF-B. This was confirmed through identification of a
motif with NF-B–like binding activity in the human IAP-1 promoter
region. Moreover, antisense inhibition of IAP-1 sensitized high-density
SMCs to the induction of cell death. Together, our data imply that SMCs
at high density are protected by an antiapoptotic mechanism
that involves increased expression of NF-B and IAP-1. Interference
with pathways that control the susceptibility to programmed cell death
may be helpful in the treatment of diseases where dysregulation of
apoptosis is involved, eg, atherosclerosis
and restenosis.
Key Words: apoptosis • nuclear factor-B • restenosis • gene transfer
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