CD40 is essential in the upregulation of TRAF proteins and NF-kappaB-dependent proinflammatory gene expression after arterial injury.
CD40 is essential in the upregulation of TRAF proteins and NF-kappaB-dependent proinflammatory gene expression after arterial injury.
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DOI：
10.1371/journal.pone.0023239
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Li G
中科院分区：
文献类型：
--
作者：
Song Z;Jin R;Yu S;Rivet JJ;Smyth SS;Nanda A;Granger DN;Li G
尽管进行了广泛的研究，但血管介入治疗后的再狭窄仍然是一个未解决的临床问题，其主要特征是新生内膜形成。最近的一项研究表明，通过TNF受体相关因子6（TRAF 6）的CD 40信号转导在颈动脉损伤后新生内膜形成中起着关键作用;然而，其潜在机制尚未明确阐明。由于新生内膜形成可能因损伤类型而显着不同，我们首先在颈动脉结扎和股动脉剥脱损伤2种损伤模型中评估了CD 40缺乏对新生内膜形成的影响。与野生型小鼠相比，CD 40缺陷显著减少了两种不同模型中的新生内膜形成和管腔狭窄。此外，我们研究了CD 40信号传导影响动脉损伤后新生内膜形成的机制。在野生型小鼠中，在颈动脉结扎后3-7天内，颈动脉中CD 40、几种TRAF蛋白（包括TRAF 1、TRAF 2、TRAF 3、TRAF 5和TRAF 6）以及总NF-κ B p65和磷酸化NF-κ B p65的表达水平显著上调。CD 40的缺乏消除了损伤诱导的TRAFs的上调，包括TRAF 6和NF-kB-p65在损伤的血管壁。此外，CD 40 −/−小鼠显示中性粒细胞的募集显著减少，结果表明，TNF-α、IL-1β、IL-6、MCP-1、ICAM-1、VCAM-1等细胞因子和巨噬细胞均能抑制NF-κ B的活化，降低NF-κ B相关基因的表达。此外，在CD 40缺陷小鼠中，巯基乙酸盐诱导的腹膜炎模型中的中性粒细胞募集受损。体外实验结果显示，CD 40缺乏可阻断CD 40 L诱导的白细胞NF-κ B p65核转位。总之，我们的数据首次确定了CD 40在体内TRAF 6，NF-kB活化和NF-kB依赖性促炎基因的上调中是必不可少的。我们的研究结果在2种不同的损伤模型中牢固地确立了CD 40在新生内膜形成中的作用。
Despite extensive investigations, restenosis, which is characterized primarily by neointima formation, remains an unsolved clinical problem after vascular interventions. A recent study has shown that CD40 signaling through TNF receptor associated factor 6 (TRAF6) plays a key role in neointima formation after carotid artery injury; however, underlying mechanisms are not clearly elucidated. Because neointima formation may vary significantly depending on the type of injury, we first assessed the effect of CD40 deficiency on neointima formation in 2 injury models, carotid artery ligation and femoral artery denudation injury. Compared with wild-type mice, CD40 deficiency significantly reduced neointima formation and lumen stenosis in two different models. Further, we investigated the mechanism by which CD40 signaling affects neointima formation after arterial injury. In wild-type mice, the expression levels of CD40, several TRAF proteins, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6, as well as total NF-kB p65 and phospho-NF-kB p65, in the carotid artery were markedly upregulated within 3–7 days after carotid ligation. Deficiency of CD40 abolished the injury-induced upregulation of TRAFs including TRAF6 and NF-kB-p65 in the injured vessel wall. Further, CD40−/− mice showed a significant decrease in the recruitment of neutrophils (at 3, 7d) and macrophages (at 7, 21d) into injured artery; this effect was most likely attributed to inhibition of NF-kB activation and marked downregulation of NF-kB-related gene expression, including cytokines (TNFα, IL-1β, IL-6), chemokines (MCP-1), and adhesion molecules (ICAM-1, VCAM-1). Moreover, neutrophil recruitment in a model of thioglycollate-induced peritonitis is impaired in CD40-deficient mice. In vitro data revealed that CD40 deficiency blocked CD40L-induced NF-kB p65 nuclear translocation in leukocytes. Altogether, our data identified for the first time that CD40 is essential in the upregulation of TRAF6, NF-kB activation, and NF-kB-dependent proinflammatory genes in vivo. Our findings firmly established the role for CD40 in neointima formation in 2 distinct injury models.
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DOI：
10.1161/atvbaha.107.144576
发表时间：
2007-08-01
影响因子：
8.7
作者：
Li, Guohong;Keenan, Alison C.;Smyth, Susan S.
通讯作者：
Smyth, Susan S.
DOI：
10.1161/01.atv.17.10.2238
发表时间：
1997-10-01
影响因子：
8.7
作者：
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影响因子：
37.8
作者：
Iwata, Hiroshi;Manabe, Ichiro;Nagai, Ryozo
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影响因子：
4.8
作者：
He, Jeannie Q.;Saha, Supriya K.;Cheng, Genhong
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