Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation
Factor Xa stimulates fibroblast procollagen production, proliferation, and calcium signaling via PAR1 activation
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DOI：
10.1016/j.yexcr.2004.10.021
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发表时间：
2005-03-10
影响因子：
3.7
通讯作者：
Chambers, RC
中科院分区：
文献类型：
--
作者：
Blanc-Brude, OP;Archer, F;Chambers, RC
成纤维细胞增殖和前胶原蛋白的产生是组织修复和纤维化的中心特征。除了在凝血中的作用外，凝血级联蛋白酶凝血酶还可通过蛋白酶激活受体-1（PAR（1））的蛋白水解激活刺激成纤维细胞，从而促进组织修复。在止血过程中，凝血级联蛋白酶因子X转化为因子Xa。我们以前已经表明，Xa因子通过产生自分泌PDGF上调成纤维细胞增殖。在这项研究中，我们进一步研究了Xa因子对成纤维细胞功能的影响，并旨在确定其信号受体。我们发现，因子Xa刺激人和小鼠成纤维细胞的前胶原启动子活性和蛋白质生产。这种效果是独立的PDGF和凝血酶的生产，但依赖于因子Xa蛋白水解活性。我们还发现PAR（1）缺陷的小鼠成纤维细胞对Xa因子的反应不上调前胶原的产生，不动员胞浆钙，也不增殖。脱敏技术和PAR（1）特异性激动剂和抑制剂用于证明PAR介导人成纤维细胞中Xa因子信号传导。这是第一次报道Xa因子刺激细胞外基质的产生。与内皮细胞和血管平滑肌细胞相反，成纤维细胞似乎是唯一一种Xa因子的作用主要通过PAR（1）而不是PAR（2）介导的细胞类型。这些发现对于我们理解组织修复和纤维化机制，以及设计新的方法来抑制凝血级联的促纤维化作用而不影响血液止血至关重要。(C)2004年爱思唯尔公司All rights reserved.
Fibroblast proliferation and procollagen production are central features of tissue repair and fibrosis. In addition to its role in blood clotting, the coagulation cascade proteinase thrombin can contribute to tissue repair by stimulating fibroblasts via proteolytic activation of proteinase-activated receptor-1 (PAR(1)). During hemostasis, the coagulation cascade proteinase factor X is converted into factor Xa. We have previously shown that factor Xa upregulates fibroblast proliferation via production of autocrine PDGF. In this study, we further examined the effects of factor Xa on fibroblast function and aimed to identify its signaling receptor. We showed that factor Xa stimulates procollagen promoter activity and protein production by human and mouse fibroblasts. This effect was independent of PDGF and thrombin production, but dependent on factor Xa proteolytic activity. We also showed that PAR(1)-deficient mouse fibroblasts did not upregulate procollagen production, mobilize cytosolic calcium, or proliferate in response to factor Xa. Desensitization techniques and PAR(1)-specific agonists and inhibitors were used to demonstrate that PAR, mediates factor Xa signaling in human fibroblasts. This is the first report that factor Xa stimulates extracellular matrix production. In contrast with endothelial cells and vascular smooth muscle cells, fibroblasts appear to be the only cell type in which the effects of factor Xa are mediated mainly via PAR(1) and not PAR(2). These findings are critical for our understanding of tissue repair and fibrotic mechanisms, and for the design of novel approaches to inhibit the profibrotic effects of the coagulation cascade without compromising blood hemostasis. (C) 2004 Elsevier Inc. All rights reserved.