NF-κB:: pivotal mediator or innocent bystander in atherogenesis?
NF-κB:: pivotal mediator or innocent bystander in atherogenesis?
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DOI：
10.1172/jci10373
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发表时间：
2001-02-01
影响因子：
15.9
通讯作者：
Cybulsky, MI
中科院分区：
文献类型：
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作者：
Collins, T;Cybulsky, MI
NF-κB在防御和病变的血管内膜平滑肌细胞中均含有REL蛋白，提示转录因子被激活。最近，在高胆固醇饮食的猪的冠状动脉内膜细胞中发现了激活的NF-κB[4]。在动脉损伤模型中，NF-κB在血管内皮细胞和血管内皮细胞均被激活。总之，这些观察结果支持了核因子-κB在动脉粥样硬化中的作用。其产物可能参与动脉粥样硬化过程的多个基因受核因子-κB的调节。白细胞黏附分子，如血管细胞黏附分子-1、细胞间黏附分子-1和E-选择素，以及趋化因子单核细胞趋化蛋白-1和白介素8，帮助循环中的单核细胞向动脉内膜募集。组织因子等其他依赖于NF-κB的基因的诱导可使内皮细胞表面的促/抗凝血剂平衡向凝血方向倾斜。靶基因的其他产物，包括细胞周期蛋白D1，可能会在病变形成部位诱导细胞增殖或刺激细胞存活(见下文)。总之，NF-κB依赖基因的协同诱导可能在血管壁上发挥重要的致动脉粥样硬化作用。如果这种反应持续下去，可能会刺激平滑肌细胞的迁移和增殖，以及循环中单核细胞的持续募集。这些细胞的激活反过来可以导致额外的细胞因子和趋化因子的释放，以及生长因子的产生。因此，在病变的扩展和进展过程中，核因子-κB可能对动脉粥样硬化信号的初始反应和随后的放大步骤都是关键。血管细胞黏附分子-1在动脉粥样硬化病变形成部位的诱导是早期动脉粥样硬化病变形成过程中可诱导的NF-κB依赖基因表达的一个例子。血管细胞黏附分子-1(VCAM-1)是一种黏附分子，由炎性细胞因子诱导内皮细胞、血管内皮细胞和一些非血管细胞表达。它在动脉粥样硬化动物模型和人体组织中的表达已经得到了广泛的研究。这些研究为该基因的潜在病理生理功能以及NF-κB的激活提供了深入的见解，因为VCAM1的启动子包含两个共同的NF-κB位点，这两个位点是细胞因子诱导表达所必需的。在正常的小鼠和兔的主动脉中，只有在容易形成动脉粥样硬化病变的部位的内皮细胞中才发现低水平的VCAM-1[5]。无论是载脂蛋白E基因敲除小鼠(apoE-/-)还是胆固醇喂养的兔，高胆固醇血症都会上调
NF-κB in defense and disease of intimal smooth muscle cells contain both Rel proteins, suggesting that the transcription factor is activated. More recently, activated NF-κB was detected in intimal cells found in coronary arteries of pigs placed on a hypercholesterolemic diet (4). In models of arterial injury, NF-κB is activated in both endothelial and smooth muscle cells. Collectively, these observations support a role for NF-κB in atherosclerosis. Multiple genes whose products are putatively involved in the atherosclerotic process are regulated by NF-κB. Leukocyte adhesion molecules, such as VCAM-1, ICAM-1, and E-selectin, as well as the chemokines (chemoattractant cytokines) monocyte chemoattractant protein-1 (MCP-1) and IL-8, help recruit circulating mononuclear leukocytes to the arterial intima. The induction of other NF-κB–dependent genes such as tissue factor could tip the pro/anti-coagulant balance on the endothelial cell surface towards coagulation. Still other products of target genes, including cyclin D1, may induce cell proliferation or stimulate cell survival at the sites of lesion formation (see below). Collectively, the coordinate induction of NF-κB–dependent genes may exert a substantial atherogenic effect on the vessel wall. If the response persists, it may stimulate migration and proliferation of smooth muscle cells, as well as ongoing recruitment of circulating monocytes. Activation of these cells, in turn, can lead to the release of additional cytokines and chemokines, as well as the production of growth factors. Therefore, NF-κB may be key both to initial responses to the atherogenic signal and to subsequent amplification steps during the expansion and progression of lesions. The induction of VCAM-1 at sites of atherosclerotic lesion formation is an example of inducible NF-κB–dependent gene expression during formation of early atherosclerotic lesions. VCAM-1 is an adhesion molecule whose expression is induced by inflammatory cytokines on endothelial, smooth muscle, and some nonvascular cells. Its expression has been studied extensively in animal models of atherogenesis and in human tissues. These studies provide insights into potential pathophysiological functions of this gene as well as NF-κB activation, since the promoter of VCAM1 contains two consensus NF-κB sites that are required for cytokine-induced expression. In normal mouse and rabbit aortas, low levels of VCAM-1 are found in endothelium only at sites predisposed to atherosclerotic lesion formation (5). Hypercholesterolemia, whether in apoE knockout (apoE–/–) mice or cholesterol-fed rabbits, upregulates