The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.
The subendothelial extracellular matrix modulates NF-kappaB activation by flow: a potential role in atherosclerosis.
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DOI：
10.1083/jcb.200410073
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发表时间：
2005-04-11
影响因子：
7.8
通讯作者：
Schwartz, Martin Alexander
中科院分区：
文献类型：
--
作者：
Orr, A Wayne;Sanders, John M;Bevard, Melissa;Coleman, Elizabeth;Sarembock, Ian J;Schwartz, Martin Alexander
动脉粥样硬化斑块形成于暴露于扰动流的脉管系统的区域中。NF-κB通过流体流动激活，导致靶基因如E-选择素、ICAM-1和VCAM-1的表达，可能调节早期单核细胞募集和脂肪条纹形成。流动诱导的NF-κB活化是整合素构象活化的下游，导致新的整合素结合到内皮下细胞外基质和信号传导。因此，我们研究了细胞外基质在这一过程中的参与。尽管铺在纤连蛋白或纤维蛋白原上的内皮细胞响应于流动而激活NF-κB，但胶原或层粘连蛋白上的细胞不会。在体内，纤连蛋白和纤维蛋白原在动脉粥样硬化的其他迹象之前沉积在动脉粥样硬化的易发部位。胶原上整合素α2β1的连接通过在粘附位点局部激活的p38依赖性途径阻止流动诱导的NF-κB激活。此外，改变细胞外基质以促进纤连蛋白上的细胞中的p38活化抑制NF-κB活化，这提示了治疗动脉粥样硬化的新的治疗策略。
Atherosclerotic plaque forms in regions of the vasculature exposed to disturbed flow. NF-κB activation by fluid flow, leading to expression of target genes such as E-selectin, ICAM-1, and VCAM-1, may regulate early monocyte recruitment and fatty streak formation. Flow-induced NF-κB activation is downstream of conformational activation of integrins, resulting in new integrin binding to the subendothelial extracellular matrix and signaling. Therefore, we examined the involvement of the extracellular matrix in this process. Whereas endothelial cells plated on fibronectin or fibrinogen activate NF-κB in response to flow, cells on collagen or laminin do not. In vivo, fibronectin and fibrinogen are deposited at atherosclerosis-prone sites before other signs of atherosclerosis. Ligation of integrin α2β1 on collagen prevents flow-induced NF-κB activation through a p38-dependent pathway that is activated locally at adhesion sites. Furthermore, altering the extracellular matrix to promote p38 activation in cells on fibronectin suppresses NF-κB activation, suggesting a novel therapeutic strategy for treating atherosclerosis.