Nuclear factor-kappa B regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells

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.