Nuclear factor-κB regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells
Nuclear factor-κB regulates induction of apoptosis and inhibitor of apoptosis protein-1 expression in vascular smooth muscle cells
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DOI：
10.1161/01.res.84.6.668
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发表时间：
1999-04-02
影响因子：
20.1
通讯作者：
Weber, C
中科院分区：
文献类型：
--
作者：
Erl, W;Hansson, GK;Weber, C
细胞凋亡在正常发育以及动脉粥样硬化等疾病中是重要的。然而，细胞凋亡的调控仍然没有完全理解。我们现在发现，转录因子核因子-κ B（NF-κ B）控制人和大鼠血管平滑肌细胞（SMC）凋亡的诱导。高密度培养的平滑肌细胞显示出高的NF-κ B B活性，对诱导凋亡不敏感。通过腺病毒介导的NF-κ B抑制剂I κ B α的过表达抑制NF-κ B，在低细胞密度下引起细胞死亡显著增加，但在高细胞密度下不引起。通过用蛋白酶体抑制剂抑制内源性I κ B α的降解来提高内源性I κ B α的水平，导致低密度SMC的凋亡诱导，如通过增加膜联蛋白V的结合、降低线粒体膜电位和增加亚二倍体DNA所检测到的。在高密度培养中，细胞凋亡的保护作用与凋亡抑制蛋白-1（IAP-1）的表达有关。I κ B α的转移降低了人IAP-1 mRNA水平，这表明IAP-1受NF-κ B的转录调控。这通过鉴定人IAP-1启动子区域中具有NF-κ B样结合活性的基序得到证实。此外，IAP-1的反义抑制使高密度SMC对细胞死亡的诱导敏感。总之，我们的数据表明，在高密度的SMC的保护，涉及增加NF-κ B和IAP-1的表达的抗凋亡机制。干预控制细胞程序性死亡易感性的途径可能有助于治疗涉及凋亡失调的疾病，例如动脉粥样硬化和再狭窄。
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-kappa B (NF-kappa B) controls the induction of apoptosis in human and rat vascular smooth muscle cells (SMCs). SMCs in high-density culture exhibited a high NF-kappa B activity and were insensitive to induction of apoptosis. Inhibition of NF-kappa B by adenovirus-mediated overexpression of its inhibitor I kappa B alpha caused a marked increase in cell death at low but not high cell density. Elevating endogenous I kappa B alpha 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 apnptosis protein-1 (IAP-1). Transfer of I kappa B alpha reduced human IAP-1 mRNA levels, which suggested that IAP-1 is transcriptionally regulated by NF-kappa B. This was confirmed through identification of a motif with NF-kappa 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-kappa 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.