Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue
Coagulation factor Xa induces an inflammatory signalling by activation of protease-activated receptors in human atrial tissue
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DOI：
10.1016/j.ejphar.2013.09.006
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发表时间：
2013-10-15
影响因子：
5
通讯作者：
Goette, Andreas
中科院分区：
文献类型：
--
作者：
Bukowska, Alicja;Zacharias, Ines;Goette, Andreas
活化因子X（FXa）是负责凝血酶生成的凝血级联反应中的重要参与者，其在房颤期间被激活。越来越多的证据表明，FXa通过激活蛋白酶激活受体（PARS）影响各种细胞类型中的细胞信号传导。目前尚不清楚FXa的分子效应是否影响心房信号转导。为了研究FXa的作用，将人心房组织切片与EXa培养长达24小时。此外，以4 Hz的频率进行快速起搏，以模拟房颤。在实验条件下分析FXa拮抗剂（利伐沙班）、蛋白酶激活受体1拮抗剂（SCH 79797）和蛋白酶激活受体2拮抗剂（GB 83）的抑制作用。心房组织暴露于FXa导致PAR 2-mRNA上调1.7倍，MAP激酶（ERK 1/2）和NF-κ B信号传导激活。此外，EXa增加粘附分子ICAM-1（1.82垂直于0.20）、趋化因子IL-8（1.94垂直于0.20）以及促血栓形成分子派-1（1.52 +/-0.17）的表达。快速起搏和FXa的组合引起PAR 1（2.82 +/- 0.22）、PAR 2（2.66 +/- 0.40）、ICAM-1（2.13 +/-0.25）的显著上调。IL-8（222 +/- 0.24）、LOX-1（2.59 +/- 0.35）和派-1（2.65 +/- 0.52）在mRNA水平。利伐沙班和GB 83阻止PAR、ICAM-1、LOX-1、IL-8的上调和MAP激酶的活化。在SCH 79797或利伐沙班的存在下，派-1表达的升高受到阻碍。本研究表明，FXa介导心房组织中的炎症信号。重要的是，FXa和快速性心律失常协同作用，以增加蛋白酶激活受体和炎症介质的表达。利伐沙班有效地防止了人心房组织中FXa诱导的分子效应，特别是在快速起搏期间。(C)2013作者出版社：Elsevier B. V.版权所有，
Activated factor X (FXa) is an important player in the coagulation cascade responsible for thrombin generation, which is activated during atrial fibrillation. Increasing evidence suggests that FXa influences cell signalling in various cell types by activating protease-activated receptors (PARS). It is so far not known if molecular effects of FXa affect atrial signal transduction. To study the effects of FXa, human atrial tissue slices were cultivated with EXa up to 24 h. Additionally, rapid pacing was applied at 4 Hz to resemble atrial fibrillation. The inhibitory impact of FXa antagonist (Rivaroxaban), protease-activated receptor 1 antagonist (SCH79797), and protease-activated receptor 2 antagonist (GB83) were analysed under experimental conditions. The exposure of atrial tissue to FXa resulted in the 1.7 fold upregulation of PAR2-mRNA, activation of MAP kinases (ERK1/2) and NF-kappa B signalling. Furthermore EXa increased the expression of adhesion molecule ICAM-1 (1.82 perpendicular to 0,20), chemokine IL-8 (1.94 perpendicular to 020), as well as prothrombotic molecule PAI-1 (1.52 +/- 0.17). The combination of rapid pacing and FXa caused significant upregulation of PAR1 (2.82 +/- 0.22), PAR2 (2.66 +/- 0.40), ICAM-1 (2,13 +/- 025). IL-8 (222 +/- 0.24), LOX-1 (2.59 +/- 0.35), and PAI-1 (2.65 +/- 0.52) at the mRNA level. Rivaroxaban and GB83 prevented upregulation of PARs, ICAM-1, LOX-1, IL-8, and activation of MAP kinases. The elevation in the expression of PAI-1 was hindered in the presence of SCH79797, or Rivaroxaban. The present study indicates that FXa mediates inflammatory signalling in atrial tissue. Importantly, FXa and tachyarrhythmia act synergistically to increase expression of protease-activated receptors and inflammatory mediators. Rivaroxaban prevented effectively FXa-induced molecular effects in human atrial tissue particularly during rapid pacing. (C) 2013 The Authors. Published by Elsevier B.V. All rights reserved,