Bu De-xiu, Erl Wolfgang, de Martin Rainer, Hansson Göran K, Yan Zhong-qun
Cardiovascular Research Unit L8:03, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
FASEB J. 2005 Aug;19(10):1293-5. doi: 10.1096/fj.04-2645fje. Epub 2005 Jun 6.
Nuclear factor-kappaB (NF-kappaB)-mediated vascular inflammation is a prominent characteristic of atherogenesis and restenosis. We noted that angioplastic injury to carotid artery elicited two phases of NF-kappaB activation characterized by an early activation in the arterial media and a late activation coupled with high levels of inhibitor of IkappaB kinase (IKK) activity in intima. These findings prompted us to elucidate the role for the different phases of NF-kappaB activation and IKK in the progress of vascular repair. Our results show that blockade of the early NF-kappaB activation by perivascular administration of pyrrolidine dithiocarbamate transiently attenuates the expression of proinflammatory genes in the injured vessels but does not affect intimal formation. Interruption of IKKbeta by overexpressing a dominant-negative IKKbeta in the injured artery effectively inhibited the late phase of NF-kappaB activation, resulting in down-regulation of inducible nitric oxide synthase, tumor necrosis factor alpha, and monocyte chemoattractant protein-1 expression in conjunction with a 36% reduction in intima size, albeit with a lack of inhibitory effect on the early NF-kappaB activation. Collectively, these findings show that the IKKbeta-mediated late-phase NF-kappaB activation contributes to intimal hyperplasia and the accompanied vascular inflammatory responses.
核因子-κB（NF-κB）介导的血管炎症是动脉粥样硬化和再狭窄的一个突出特征。我们注意到，颈动脉血管成形术损伤引发了NF-κB激活的两个阶段，其特征为动脉中膜的早期激活以及内膜中与高水平IκB激酶（IKK）活性相关的晚期激活。这些发现促使我们阐明NF-κB激活和IKK不同阶段在血管修复过程中的作用。我们的结果表明，通过血管周围给予吡咯烷二硫代氨基甲酸盐阻断早期NF-κB激活可短暂减弱损伤血管中促炎基因的表达，但不影响内膜形成。在损伤动脉中过表达显性负性IKKβ以阻断IKKβ，可有效抑制NF-κB激活的晚期阶段，导致诱导型一氧化氮合酶、肿瘤坏死因子α和单核细胞趋化蛋白-1表达下调，同时内膜大小减少36%，尽管对早期NF-κB激活缺乏抑制作用。总体而言，这些发现表明IKKβ介导的晚期NF-κB激活促成内膜增生及伴随的血管炎症反应。
