Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing Kruppel-like factor 2.
Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing Kruppel-like factor 2.
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DOI：
10.1161/circresaha.111.256362
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发表时间：
2012-02-17
影响因子：
20.1
通讯作者：
Berk BC
中科院分区：
文献类型：
--
作者：
Wang XQ;Nigro P;World C;Fujiwara K;Yan C;Berk BC
暴露于血流紊乱（d-flow）区域的内皮细胞（EC）容易发生炎症并随后发生动脉粥样硬化。我们之前表明，硫氧还蛋白相互作用蛋白（TXNIP）是肿瘤坏死因子（TNF）介导的血管细胞粘附分子（VCAM）-1表达所必需的。我们试图研究 TXNIP 在 d 流诱导的细胞粘附分子表达和白细胞与血管相互作用中的作用，以及 TXNIP 抑制动脉粥样硬化保护基因表达的机制。使用小鼠主动脉的正面染色，我们发现与稳定流（s-flow）相比，暴露于 d-flow 的部位 EC 中的 TXNIP 显着增加。 EC 特异性 TXNIP 敲除 (ECTXNIP KO) 小鼠显示小鼠主动脉 d 流区域中 VCAM-1 和细胞间粘附分子 1 (ICAM-1) mRNA 表达显着降低。肠系膜微静脉活体显微镜观察显示，EC-TXNIP KO小鼠白细胞滚动时间减少，而滚动速度显着增加。利用切口流动室产生不同流动模式的体外实验表明，d 流诱导的 EC-单核细胞粘附需要增加 TXNIP。此外，我们发现 EC 中关键的抗炎转录因子 Kruppel 样因子 2 (KLF2) 的表达被 TXNIP 抑制。荧光素酶和染色质免疫沉淀 (ChIP) 测定表明 TXNIP 存在于 KLF2 启动子上的抑制复合物中。这些数据证明了 TXNIP 在介导 d-flow 下 EC-白细胞粘附方面的重要作用，并定义了 TXNIP 作为转录辅阻遏物来调节 KLF2 依赖性基因表达的新机制。
Endothelial cells (EC) at regions exposed to disturbed flow (d-flow) are predisposed to inflammation and the subsequent development of atherosclerosis. We previously showed that thioredoxin interacting protein (TXNIP) was required for tumor necrosis factor (TNF)-mediated expression of vascular cell adhesion molecule (VCAM)-1. We sought to investigate the role of TXNIP in d-flow-induced cell adhesion molecule expression and leukocyte interaction with vessels, and the mechanisms by which TXNIP suppresses athero-protective gene expression. Using en face staining of mouse aorta, we found a dramatic increase of TXNIP in EC at sites exposed to d-flow as compared to steady flow (s-flow). EC-specific TXNIP knockout (ECTXNIP KO) mice showed significant decreases in VCAM-1 and intercellular adhesion molecule-1 (ICAM-1) mRNA expression in the d-flow regions of mouse aorta. Intravital microscopy of mesenteric venules showed that leukocyte rolling time was decreased, while rolling velocity was increased significantly in EC-TXNIP KO mice. In vitro experiments utilizing a cutout flow chamber to generate varying flow patterns showed that increased TXNIP was required for d-flow-induced EC-monocyte adhesion. Furthermore, we found that the expression of Kruppel-like factor 2 (KLF2), a key anti-inflammatory transcription factor in EC, was inhibited by TXNIP. Luciferase and chromatin immunoprecipitation (ChIP) assays showed that TXNIP was present within a repressing complex on the KLF2 promoter. These data demonstrate the essential role for TXNIP in mediating EC-leukocyte adhesion under d-flow, as well as define a novel mechanism by which TXNIP acts as a transcriptional corepressor to regulate KLF2-dependent gene expression.