Reciprocal Regulation of Rac1 and PAK-1 by HIF-1α: A Positive-Feedback Loop Promoting Pulmonary Vascular Remodeling
Reciprocal Regulation of Rac1 and PAK-1 by HIF-1α: A Positive-Feedback Loop Promoting Pulmonary Vascular Remodeling
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DOI：
10.1089/ars.2009.3013
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发表时间：
2010-08-01
影响因子：
6.6
通讯作者：
Goerlach, Agnes
中科院分区：
文献类型：
--
作者：
Diebold, Isabel;Petry, Andreas;Goerlach, Agnes
与肺动脉高压相关的肺血管重构的特征是中膜增厚、增生紊乱和原位血栓形成。p21激活激酶-1（PAK-1）可调控生长、迁移和促血栓形成活性，而缺氧诱导转录因子HIF-1 α与肺血管重塑相关。在这里，我们研究了PAK-1和HIF-1 α是否与肺血管重塑有关。PAK-1在肺血管病变患者的重塑肺血管中表达，并在肺血管重塑的羔羊肺组织中与其上游调节因子Rac 1和HIF-1 α一起上调。人肺动脉平滑肌细胞（PASMCs）中PAK-1和Rac 1被凝血酶激活，从而导致活性氧（ROS）的产生增加。PAK-1的激活刺激HIF-1活性和HIF-1 α表达，包括ROS和NF-κ B，增强HIF-1靶基因纤溶酶原激活物抑制剂-1的表达，并刺激PASMC增殖。重要的是，HIF-1本身与Rac 1启动子结合，增强Rac 1和PAK-1的转录。因此，PAK-1及其激活剂Rac 1是新的HIF-1靶点，可能构成凝血酶和ROS诱导HIF-1 α的正反馈回路，从而解释了重塑肺血管中PAK-1、Rac 1和HIF-1 α水平升高的原因。抗氧化剂。氧化还原信号。13，399-412。
Pulmonary vascular remodeling associated with pulmonary hypertension is characterized by media thickening, disordered proliferation, and in situ thrombosis. The p21-activated kinase-1 (PAK-1) can control growth, migration, and prothrombotic activity, and the hypoxia-inducible transcription factor HIF-1 alpha was associated with pulmonary vascular remodeling. Here we studied whether PAK-1 and HIF-1 alpha are linked in pulmonary vascular remodeling. PAK-1 was expressed in the media of remodeled pulmonary vessels from patients with pulmonary vasculopathy and was upregulated, together with its upstream regulator Rac1 and HIF-1 alpha in lung tissue from lambs with pulmonary vascular remodeling. PAK-1 and Rac1 were activated by thrombin involving calcium, thus resulting in enhanced generation of reactive oxygen species (ROS) in human pulmonary artery smooth muscle cells (PASMCs). Activation of PAK-1 stimulated HIF activity and HIF-1 alpha expression involving ROS and NF-kappa B, enhanced the expression of the HIF-1 target gene plasminogen activator inhibitor-1, and stimulated PASMC proliferation. Importantly, HIF-1 itself bound to the Rac1 promoter and enhanced Rac1 and PAK-1 transcription. Thus, PAK-1 and its activator Rac1 are novel HIF-1 targets that may constitute a positive-feedback loop for induction of HIF-1 alpha by thrombin and ROS, thus explaining elevated levels of PAK-1, Rac1, and HIF-1 alpha in remodeled pulmonary vessels. Antioxid. Redox Signal. 13, 399-412.