A novel mechanism of plasmin-induced mitogenesis in fibroblasts
A novel mechanism of plasmin-induced mitogenesis in fibroblasts
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DOI：
10.1111/j.1538-7836.2004.01054.x
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发表时间：
2005-01-01
影响因子：
10.4
通讯作者：
Pendurthi, JR
中科院分区：
文献类型：
--
作者：
Mandal, SK;Rao, LVM;Pendurthi, JR
纤溶酶原激活剂/纤溶酶系统被认为在多种病理生理过程中发挥重要作用，包括伤口愈合、血管重塑和肺纤维化。我们最近的研究表明，纤溶蛋白上调Cyr61的表达，Cyr61是一种与细胞增殖和迁移有关的生长因子样基因。在本研究中，我们研究了纤溶蛋白是否促进成纤维细胞增殖，如果是，确定Cyr61在纤溶蛋白诱导的反应中的作用。将人肺成纤维细胞暴露于不同浓度的纤溶酶中，通过测量3 h -胸腺嘧啶与DNA的结合来监测DNA的合成。纤溶酶以剂量依赖的方式增加成纤维细胞的DNA合成。蛋白酶激活受体-1 （PAR-1）特异性抗体，而不是par -2特异性抗体，减少了纤溶蛋白诱导的DNA合成。与此一致的是，纤溶酶对par -1缺陷小鼠成纤维细胞的DNA合成没有实质性影响。纤溶蛋白激活了p38和p44/42 MAPKs，这些途径的特异性抑制剂抑制了纤溶蛋白诱导的DNA合成。抗cyr61抗体完全消除了纤溶蛋白诱导的DNA合成增加。有趣的是，凝血酶是Cyr61的有效诱导剂，对成纤维细胞增殖的影响很小。进一步的实验表明，纤溶酶可切割细胞/细胞外基质相关的Cyr61，而纤溶酶处理细胞的条件培养基可支持细胞增殖。总的来说，这些数据表明，纤溶酶通过一个新的途径促进成纤维细胞增殖，涉及两个独立的步骤。第一步，纤溶蛋白通过激活PAR-1诱导Cyr61表达，第二步，纤溶蛋白释放沉积在细胞外基质中的Cyr61，从而使其能够作用于细胞。
The plasminogen activator/plasmin system is believed to play an important role in diverse pathophysiological processes, including wound healing, vascular remodeling and pulmonary fibrosis. Our recent studies show that plasmin upregulates the expression of Cyr61, a growth factor-like gene that has been implicated in cell proliferation and migration. In the present study, we investigated whether plasmin promotes fibroblast proliferation and, if so, determine the role of Cyr61 in the plasmin-induced response. Human lung fibroblasts were exposed to varying concentrations of plasmin and DNA synthesis was monitored by measuring the incorporation of 3 H-thymidine into DNA. Plasmin increased DNA synthesis of fibroblasts in a dose-dependent manner. Protease-activated receptor-1 (PAR-1)-specific antibodies, but not PAR-2-specific antibodies, reduced the plasmin-induced DNA synthesis. Consistent with this, plasmin had no substantial effect on the DNA synthesis in PAR-1-deficient mouse fibroblasts. Plasmin activated both p38 and p44/42 MAPKs and specific inhibitors of these pathways inhibited the plasmin-induced DNA synthesis. Plasmin-induced increase in the DNA synthesis was completely abrogated by anti-Cyr61 antibodies. Interestingly, thrombin, which is a potent inducer of Cyr61, had only a minimal effect on fibroblast proliferation. Additional experiments suggested that plasmin cleaved cell/extracellular matrix-associated Cyr61 and the conditioned media from plasmin-treated cells could support the cell proliferation. Overall, these data suggest that plasmin promotes fibroblast proliferation by a novel pathway, involving two independent steps. In the first step, plasmin induces Cyr61 expression via activation of PAR-1, and in the second step, plasmin releases Cyr61 deposited in the extracellular matrix, thus making it accessible to act on cells.