Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells.
Antithrombotic Effects of Nur77 and Nor1 Are Mediated Through Upregulating Thrombomodulin Expression in Endothelial Cells.
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Nur77 和 Nor1 的抗血栓作用是通过上调内皮细胞中血栓调节蛋白的表达来介导的。
DOI：
10.1161/atvbaha.115.306891
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发表时间：
2016-02
期刊：
影响因子：
--
通讯作者：
Sun J
中科院分区：
文献类型：
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作者：
Yang P;Wei X;Zhang J;Yi B;Zhang GX;Yin L;Yang XF;Sun J
血栓调节蛋白（TM）在血管内皮细胞（EC）的管腔表面高度表达，并在血管壁中具有有效的抗凝、抗纤维蛋白溶解和抗炎活性。然而，TM在EC中的表达的调节在很大程度上仍然未知。在本研究中，我们的特点是核受体4A（NR 4A）家族作为一个新的调节TM表达的血管内皮细胞。我们证明了NR 4A受体Nur 77和Nor 1在腺病毒介导的Nur 77和Nor 1 cDNA转导后，在人血管内皮细胞和小鼠肝组织中强烈增加TM mRNA和蛋白水平。此外，Nur 77缺陷和Nur 77和Nor 1表达的敲低显著减弱了基础和VEGF 165刺激的TM表达。从机制上讲，我们发现Nur 77和Nor 1通过两种不同的机制来增加TM表达。我们发现，Nur 77几乎不影响TM启动子的活性，但显着增加TM mRNA的稳定性，而Nor 1增强TM的表达主要是通过诱导Kruppel样因子2和4在血管内皮细胞。此外，我们证明了Nur 77和Nor 1均显著增加蛋白C活性，并抑制肿瘤坏死因子α（TNF-α）诱导的人EC血栓前效应。Nur 77的缺乏增加了对动脉血栓形成的易感性，而Nur 77和Nor 1的表达增强保护小鼠免受动脉血栓形成。我们的研究结果确定了NR 4A受体作为血管内皮细胞中TM表达和功能的新型调节因子，并提供了一个概念验证，证明靶向增加血管内皮中Nur 77和Nor 1的表达可能代表了治疗血栓性疾病的一种新的治疗方法。
Thrombomodulin (TM) is highly expressed on the lumenal surface of vascular endothelial cells (ECs) and possesses potent anticoagulant, anti-fibrinolytic, and anti-inflammatory activities in the vessel wall. However, the regulation of TM expression in ECs remains largely unknown. In the present study, we characterized nuclear receptor 4A (NR4A) family as a novel regulator of TM expression in vascular ECs. We demonstrated that both NR4A receptor Nur77 and Nor1 robustly increase TM mRNA and protein levels in human vascular ECs and in mouse liver tissues after adenovirus-mediated transduction of Nur77 and Nor1 cDNAs. Moreover, Nur77 deficiency and knockdown of Nur77 and Nor1 expression markedly attenuated the basal and VEGF165-stimulated TM expression. Mechanistically, we found that Nur77 and Nor1 increase TM expression by acting through two different mechanisms. We show that Nur77 barely affects TM promoter activity, but significantly increases TM mRNA stability, while Nor1 enhances TM expression mainly through induction of Kruppel-like factor 2 and 4 in vascular ECs. Further, we demonstrate that both Nur77 and Nor1 significantly increase protein C activity and inhibit tumor necrosis factor alpha (TNF-α)-induced prothrombotic effects in human ECs. Deficiency of Nur77 increases susceptibility to arterial thrombosis, while enhanced expression of Nur77 and Nor1 protects mice from arterial thrombus formation. Our results identified NR4A receptors as novel regulators of TM expression and function in vascular ECs and provided a proof-of-concept demonstration that targeted increasing expression of Nur77 and Nor1 in the vascular endothelium might represent a novel therapeutic approach for the treatment of thrombotic disorders.