Involvement of the TP receptor in TNF-α-induced endothelial tissue factor expression
Involvement of the TP receptor in TNF-α-induced endothelial tissue factor expression
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DOI：
10.1016/j.vph.2014.03.007
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发表时间：
2014-08-01
影响因子：
4
通讯作者：
De Caterina, Raffaele
中科院分区：
文献类型：
--
作者：
Del Turco, Serena;Basta, Giuseppina;De Caterina, Raffaele
背景资料：血栓素（TX）A（2）、前列腺素内过氧化物和F-2-异前列腺素通过也在内皮细胞中表达的TX-前列腺素（TP）受体发挥作用。我们研究了TP受体的作用，在内皮细胞表达的组织因子（TF），一个关键的触发thrombosis.Methods和results：人脐静脉内皮细胞（HUVEC）暴露于TP受体激动剂U46619的特点是TF表面暴露和促凝血活性的浓度依赖性增加。HUVEC与TP受体拮抗剂S18886预孵育，然后用U46619或肿瘤坏死因子-α（TNF-α）刺激，与刺激对照相比，TF表面暴露和活性减弱。阿司匹林或吲哚美辛虽然抑制环氧合酶（考克斯）-1和-2活性，但不能模拟这种作用。通过选择性药理学和基因沉默实验探索潜在机制表明，S18886减少U46619或TNF-α诱导的TF表达，抑制ROS产生、NAD（P）H氧化酶和PKC活化。此外，S18886还能抑制U46619和TNF-α单独作用下ERK的激活，而抑制JNK的激活仅发生在U46619作用下。结论：内皮TP受体不仅参与已知TP受体激动剂诱导的TF表面暴露和活性，而且参与TNF-α诱导的TF表面暴露和活性。这些发现扩大了TP受体抑制的治疗潜力。(C)版权所有© 2014 Elsevier Inc.
Background: Thromboxane (TX) A(2), prostaglandin endoperoxides and F-2-isoprostanes exert their effects through a TX-prostanoid (TP) receptor, also expressed in endothelial cells. We investigated a role of the TP receptor in the endothelial expression of tissue factor (TF), a key trigger to thrombosis.Methods and results: Human umbilical vein endothelial cells (HUVEC) exposed to the TP receptor agonist U46619 featured a concentration-dependent increase in TF surface exposure and procoagulant activity. HUVEC pre-incubation with the TP receptor antagonist S18886, followed by stimulation with either U46619 or tumor necrosis factor-alpha (TNF-alpha), attenuated TF surface exposure and activity compared with stimulated control. Aspirin or indomethacin, while inhibiting cyclooxygenase (COX)-1 and -2 activities, did not mimic this effect. Probing of underlying mechanisms by selective pharmacological and gene silencing experiments showed that S18886 reduced U46619- or TNF-alpha-induced TF expression inhibiting ROS production, NAD(P)H oxidase and PKC activation. In addition, S18886 also inhibited ERK activation in the presence of both U46619 and TNF-alpha alone, while inhibition of JNK activation only occurred in the presence of U46619.Conclusion: The endothelial TP receptor contributes to TF surface exposure and activity induced not only by known TP receptor agonists, but also by TNF-alpha. Such findings expand the therapeutic potential of TP receptor inhibition. (C) 2014 Elsevier Inc All rights reserved.