Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension
Plasminogen activator inhibitor type 1 inhibits smooth muscle cell proliferation in pulmonary arterial hypertension
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DOI：
10.1016/j.biocel.2008.01.028
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发表时间：
2008-01-01
影响因子：
4
通讯作者：
Eickelberg, Oliver
中科院分区：
文献类型：
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作者：
Kouri, Fotini M.;Queisser, Markus A.;Eickelberg, Oliver
理由：血管壁内层的肺动脉平滑肌细胞（PASMCs）负责血管稳态，但也负责疾病的病理性血管重构，如特发性肺动脉高压（IPAH）。IPAH的血管重构导致血管僵硬、闭塞和血管阻力增加，但其潜在机制仍有待充分阐明。在本研究中，我们研究了纤溶酶原激活剂抑制剂(PAI)-1在IPAH患者PASMC中的表达和功能，PAI -1是纤溶酶原激活剂系统的抑制剂，也是转化生长因子(TGF)- β 1信号级联的靶基因。方法和结果：对供体和IPAH患者肺组织（n = 7）的RNA和蛋白分析显示，IPAH患者肺组织中PAI-1明显下调。免疫组化分析发现PAI-1位于支气管和肺泡上皮，以及血管和气道平滑肌细胞。与供体源性PASMC相比，来自IPAH肺的原发性PASMC中PAI-1也下调。为了阐明PAI-1的功能，用活性重组PAI-1刺激原代PASMC，或用PAI-1特异性siRNA转染。rPAI-1刺激导致PASMC增殖和对玻璃体连接蛋白的粘附减少，PASMC迁移增加。相反，PAI-1与siRNA的敲除增加了PASMC的增殖，减少了PASMC的迁移。结论：PAI-1在IPAH患者PASMC中mRNA和蛋白水平均显著下调。PAI-1负向调节PASMC增殖，同时增加PASMC迁移。因此，其在IPAH中的缺失可能导致IPAH的病理性血管重构。(C) 2008 Elsevier Ltd版权所有。
Rationale: Pulmonary arterial smooth muscle cells (PASMCs) in the medial layer of the vessel wall are responsible for vessel homeostasis, but also for pathologic vascular remodelling in diseases, such as idiopathic pulmonary arterial hypertension (IPAH). Vascular remodelling in IPAH results in vessel stiffness, occlusion, and increased vascular resistance, but its underlying mechanisms remain to be fully elucidated. In this study, we investigated the expression and function of plasminogen activator inhibitor (PAI)-1, an inhibitor of the plasminogen activator system and target gene of the transforming growth factor (TGF)-beta 1 signalling cascade, in PASMC in IPAH.Methods and results: RNA and protein analysis from lung tissues of donors and patients with IPAH (n = 7 each) revealed a significant downregulation of PAI-1 in IPAH lungs. Immunohistochemical analysis localised PAI-1 to the bronchial and alveolar epithelium, as well as to vascular and airway smooth muscle cells. PAI-1 was also downregulated in primary PASMC derived from IPAH lungs as compared with donor-derived PASMC. In order to elucidate PAI-1 function, primary PASMC were stimulated with active recombinant (r)PAI-1, or transfected with PAI-1-specific siRNA. Stimulation with rPAI-1 led to decreased PASMC proliferation and adhesion to vitronectin, and increased PASMC migration. In contrast, PAI-1 knock-down with siRNA increased PASMC proliferation and decreased PASMC migration.Conclusions: PAI-1 is significantly downregulated in PASMC in IPAH, on the mRNA and protein level. PAI-1 negatively regulates PASMC proliferation, while it increases PASMC migration. Thus, its loss in IPAH may therefore contribute to pathologic vascular remodelling in IPAH. (C) 2008 Elsevier Ltd. All rights reserved.