Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1: Role of NFκB-dependent hypoxia-inducible factor-1α transcription
Rac-1 promotes pulmonary artery smooth muscle cell proliferation by upregulation of plasminogen activator inhibitor-1: Role of NFκB-dependent hypoxia-inducible factor-1α transcription
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DOI：
10.1160/th08-07-0473
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发表时间：
2008-12-01
影响因子：
6.7
通讯作者：
Goerlach, Agnes
中科院分区：
文献类型：
--
作者：
Diebold, Isabel;Djordjevic, Talija;Goerlach, Agnes
肺血管重构通常与肺动脉高压相关，其特征在于中膜增厚和细胞增殖紊乱，通常伴有纤维蛋白沉积和原位血栓形成。然而，连接这些不同过程的信号通路并不清楚。由于GT3 Rac-1已被认为在各种细胞类型中充当信号传递中继，我们研究了Rac-1是否可能是凝血酶信号传导、纤溶酶原激活物抑制剂-1（派-1）（其抑制纤维蛋白溶解并促进纤维蛋白沉积）和肺动脉平滑肌细胞（PASMC）增殖之间的联系。暴露于凝血酶增强Rac-1蛋白的水平，并增加派-1的mRNA和蛋白的表达依赖于凝血酶受体PAR-1。显性负性Rac-1（RacT 17 N）的表达阻止凝血酶诱导的派-1表达，而组成型活性RacG 12 V增强派-1水平。在RacT 17 N凝血酶诱导的派-1启动子活性被废除，而RacG 12 V增加派-1启动子活性，这种反应基本上是依赖于转录因子缺氧诱导因子-1（HIF-1）。随后，RacG 12 V不仅增加HIF转录活性，而且增加HIF-1 α蛋白和mRNA水平，而RacT 17 N阻止凝血酶引起的这些反应。RacG 12 V增强了HIF-1 α启动子活性，这种反应依赖于核因子-κ B（NF κ B B）与HIF-1 α启动子的结合。Rac-1和HIF-1上调派-1是凝血酶刺激PASMC增殖的必要条件。这些发现表明，Rac-1是凝血酶信号传导的重要介质，并可能通过HIF-1依赖性上调派-1导致PASMC增殖增强而促进肺血管重塑。
Pulmonary vascular remodeling is commonly associated with pulmonary hypertension and is characterized by media thickening and disordered cellular proliferation, often accompanied by fibrin deposition and thrombosis in situ. However, the signaling pathways linking these different processes are not well understood. Since the GTPase Rac-1 has been suggested to act as a signaling relay in various cell types we investigated whether Rac-1 could be the link between thrombin signaling, plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis and promotes fibrin deposition, and proliferation of pulmonary artery smooth muscle cells (PASMC). Exposure to thrombin enhanced the levels of Rac-1 protein and increased PAI-1 mRNA and protein expression in dependence of the thrombin receptor PAR-1. Expression of dominant-negative Rac-1 (RacT17N) prevented thrombin-induced PAI-1 expression whereas constitutively active RacG12V enhanced PAI-1 levels. In the presence of RacT17N thrombin-induced PAI-1 promoter activity was abrogated whereas RacG12V increased PAI-1 promoter activity, and this response was essentially dependent on the transcription factor hypoxia-inducible factor-1 (HIF-1). Subsequently, RacG12V not only increased H IF transcriptional activity but also HIF-1 alpha protein and mRNA levels, whereas RacT17N prevented these responses elicited by thrombin. In line, RacG12V enhanced HIF-1 alpha promoter activity, and this response was dependent on nuclear factor-kappaB (NF kappa B) binding to the HIF-1 alpha promoter. Finally, upregulation of PAI-1 by Rac-1 and HIF-1 was essential for thrombin-stimulated proliferation of PASMC. These findings indicate that Rac-1 is an important mediator of thrombin signaling and may contribute to pulmonary vascular remodeling via HIF-1-dependent upregulation of PAI-1 leading to enhanced proliferation of PASMC.