Adiponectin inhibits tissue factor expression and enhances tissue factor pathway inhibitor expression in human endothelial cells
Adiponectin inhibits tissue factor expression and enhances tissue factor pathway inhibitor expression in human endothelial cells
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脂联素抑制人内皮细胞组织因子表达并增强组织因子途径抑制剂表达
DOI：
10.1160/th08-02-0124
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发表时间：
2008-08-01
影响因子：
6.7
通讯作者：
Chen, Fang-Ping
中科院分区：
文献类型：
--
作者：
Chen, Yi-Jian;Zhang, Li-Qun;Chen, Fang-Ping
组织因子（TF）在急性冠状动脉综合征血栓形成和动脉粥样硬化形成中起关键作用。组织因子途径抑制物（TFPI）是TF/ FVIIa复合物的特异性生理抑制剂，调节TF诱导的凝血。脂联素（Adiponectin，Adp）是一种脂肪细胞特异性的脂肪细胞因子，具有抗动脉粥样硬化和抗糖尿病的作用。Adp可抑制炎性细胞因子和粘附分子的表达，对内皮功能障碍有保护作用。本研究探讨了ADP对肿瘤坏死因子-α（TNF-α）诱导的人脐静脉内皮细胞（HU-VECs）TF和TFPI表达的影响及其信号转导途径。结果发现，ADP可显著抑制TNF-α刺激的HUVECs中TF蛋白的表达和活性。同时，它使TFPI蛋白的表达和活性增加了约两倍。ADP对TNF-α诱导的TF mRNA表达也有抑制作用，但对TFPI mRNA表达无影响。ADP对TNF-α诱导的TF表达的抑制作用可被PKA抑制剂Rp-cAMPs阻断。ADP呈剂量依赖性地增加细胞内cAMP含量和PKA活性。ADP可降低IκB-α的磷酸化，但对p44/42 MAPK、SAPK/ JNK和p38 MAPK的磷酸化无影响。这些结果表明，ADP通过抑制PKA依赖的核因子- κB（NF-κB）信号通路抑制TF表达。脂联素促进Akt和AMP活化蛋白激酶磷酸化。ADP对TNF-α诱导的TF合成的抑制作用可被PI 3激酶抑制剂LY 294002部分阻断，提示Akt活化可能抑制TNF-α诱导的TF表达。ADP的抑制作用几乎完全被cAMP/PKA途径和PI 3 K/Akt途径的抑制所消除。结论：ADP抑制TF表达的机制可能是通过稳定IκB-α和激活Akt磷酸化来抑制NF-κB的表达，但ADP增强TF PI的表达可能是通过翻译而非转录调节。
Summary Tissue factor (TF) plays a pivotal role in thrombus formation and atherogenesis in acute coronary syndrome. Tissue factor pathway inhibitor (TFPI) is a specific physiological inhibitor of TF/ FVIIa complex that regulates TF-induced coagulation. Adiponectin (Adp) is an adipocyte-specific adipocytokine with anti-atherogenic and anti-diabetic properties. Adp inhibits inflammatory cytokine and adhesion molecules expression, and it can prevent endothelial dysfunction. In this study, we investigated the effects of Adp on tumor necrosis factor-α (TNF-α)-induced expression of TF and TFPI in human umbilical vein endothelial cells (HU-VECs), and the signaling transduction pathways involved. It was found that Adp significantly inhibited both TF protein expression and activity in TNF-α-stimulated HUVECs. In the meanwhile, it increased TFPI protein expression and activity for about two folds. Adp also inhibited TF mRNA expression induced by TNF-α, but had no effect on TFPI mRNA expression. The inhibitory effect of Adp onTNF-α-inducedTF expression was prevented by pretreatment with Rp-cAMPs, a PKA inhibitor. Adp increased intracellular cAMP content and PKA activity levels in a dose-dependent manner. Phosphorylation of IκB-α was decreased by Adp, but phosphorylation of p44/42MAPK, SAPK/ JNK, and p38MAPK were not affected. These results suggested that Adp inhibits TF expression through inhibition of a PKA dependent nuclear factor- κB (NF-κB) signaling pathway. It was also found that adiponectin promoted Akt and AMP-activated protein kinase phosphorylation. The inhibitory effect of Adp on TNF-α-induced TF synthesis was abrogated in part by pretreatment with the PI3kinase inhibitor LY 294002, suggesting that Akt activation might inhibit TF expression induced by TNF-α. The inhibitory effect of Adp is almost completely abrogated by inhibition of both the cAMP/PKA pathway and PI3K/Akt pathway. In conclusion, our data indicated that inhibition of NF-κB through stabilization of IκB-α and activation of Akt phosphorylation may mediate the inhibitory effect of Adp on TF expression; but the enhancement effect of Adp on the TFPI production might occur via translational rather than transcriptional regulation.