Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1,-3 and-9 production by vascular smooth muscle cells
Inhibition of transcription factor NF-κB reduces matrix metalloproteinase-1,-3 and-9 production by vascular smooth muscle cells
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DOI：
10.1016/s0008-6363(01)00220-6
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发表时间：
2001-06-01
影响因子：
10.8
通讯作者：
Newby, AC
中科院分区：
文献类型：
--
作者：
Bond, M;Chase, AJ;Newby, AC
目的：基质金属蛋白酶（MMP）有助于破坏动脉粥样硬化斑块肩部区域的细胞外基质，导致斑块不稳定并引发临床心血管疾病。因此，人们对建立负责增加MMP产生的机制非常感兴趣。MMPs-1、MMPs-3和MMPs-9被炎性细胞因子和生长因子上调，所述炎性细胞因子和生长因子由斑块驻留巨噬细胞和平滑肌细胞产生。我们目前的研究集中在NF-κ B，它调节许多炎症基因，并在斑块平滑肌细胞中被激活。此外，NF-κ B结合位点存在于MMP-9基因的启动子中，NF-κ B样元件存在于MMP-1基因的启动子中。研究方法：我们使用腺病毒介导的其抑制剂I κ B α的过表达来研究NF-κ B在通过分离的、细胞因子刺激的兔主动脉和人隐静脉VSMC调节MMP-1、MMP-3和MMP-9中的作用。结果：IL-1 α有效激活VSMCs中的NF-κ B，并与生长因子协同作用，上调MMP-1、MMP-3和MMP-9的表达。I κ B α的过表达几乎完全抑制了响应于单独的IL-1 α或与bFGF和PDGF的组合的MMP-1、MMP-3和MMP-9的表达。结论：NF-κ B是细胞因子上调VSMC中MMP-1、MMP-3和MMP-9所必需的，这表明NF-κ B抑制可促进斑块稳定。(C)2001 Elsevier Science B. V.保留所有权利。
Objective: Matrix metalloproteinases (MMPs) contribute to the destruction of the extracellular matrix at the shoulder regions of atherosclerotic plaques that leads to plaque destabilisation and triggers clinical cardiovascular disease. There is therefore considerable interest in establishing the mechanisms responsible for increased MMP production. MMPs-1, -3 and -9 are upregulated by inflammatory cytokines and growth factors that are produced by plaque resident macrophages and smooth muscle cells. Our present studies focused an NF-kappaB, which regulates numerous inflammatory genes, and is activated in plaque smooth muscle cells. Moreover, an NF-kappaB binding site is present in the promoter of the MMP-9 gene and an NF-kappaB-like element in the promoter of the MMP-1 gene. Methods: We used adenovirus mediated overexpression of its inhibitor, I kappaB alpha to investigate the role of NF-kappaB in regulation of MMP-1, -3 and -9 by isolated, cytokine stimulated rabbit aortic and human saphenous vein VSMC. Results: IL-l alpha potently activated NF-kappaB in VSMCs and acted synergistically with growth factors to upregulate expression of MMP-1, -3 and -9. Overexpression of I kappaB alpha, almost completely inhibited expression of MMP-1, -3 and -9 in response to IL-l alpha alone or in combination with bFGF and PDGF. Conclusion: NF-kappaB is required for cytokine upregulation of MMP-1, -3 and -9 in VSMCs, which suggests that NF-kappaB inhibition may promote plaque stabilisation. (C) 2001 Elsevier Science B.V. All rights reserved.