Complement Protease MASP-1 Activates Human Endothelial Cells: PAR4 Activation Is a Link between Complement and Endothelial Function
Complement Protease MASP-1 Activates Human Endothelial Cells: PAR4 Activation Is a Link between Complement and Endothelial Function
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DOI：
10.4049/jimmunol.0900879
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发表时间：
2009-09-01
影响因子：
4.4
通讯作者：
Gal, Peter
中科院分区：
文献类型：
--
作者：
Megyeri, Marton;Mako, Veronika;Gal, Peter
补体系统的激活可以诱导和增强炎症反应。甘露糖结合凝集素相关丝氨酸蛋白酶-1（MASP-1）是补体凝集素途径中丰富的蛋白酶;然而，其生理功能尚不清楚。在这项研究中，我们首次证明MASP-I能够激活培养的HUVEC中的Ca 2+信号传导、NF-κ B和p38 MAPK通路。活化仅由MASP-1启动;相关蛋白酶MASP-2没有这种作用。该现象依赖于MASP-1的蛋白水解活性，表明通过蛋白酶活化受体（PAR）调节内皮细胞功能。使用代表PARS的蛋白酶敏感区域的合成肽底物，我们能够证明PAR 4是MASP-1的靶标。使用PAR 4激动剂肽和mRNA定量证明HUVEC中功能活性PAR 4的存在。最后，我们显示在MASP-1处理后膜结合的完整PAR 4的量减少。所有这些结果提供了内皮细胞功能调节和补体系统活化之间的新联系，并且它们表明MASP-1诱导的PAR 4活化可能有助于炎症反应的发展。免疫学杂志，2009，183：3409-3416.
Activation of the complement system can induce and enhance inflammatory reaction. Mannose-binding lectin-associated serine protease-1 (MASP-1) is an abundant protease of the complement lectin pathway; however, its physiological function is unclear. In this study, we demonstrate for the first time that MASP-I is able to activate Ca2+ signaling, NF-kappa B, and p38 MAPK pathways in cultured HUVECs. Activation was initiated by MASP-1 only; the related protease, MASP-2, had no such effect. The phenomenon was dependent on the proteolytic activity of MASP-1, suggesting modulation of endothelial cell function through a protease-activated receptor (PAR). Using synthetic peptide substrates representing the protease-sensitive regions of PARS, we were able to demonstrate that PAR4 is a target of MASP-1. The presence of functionally active PAR4 in HUVECs was demonstrated using PAR4 agonist peptide and mRNA quantification. Finally, we showed that the amount of membrane-bound intact PAR4 decreases after MASP-1 treatment. All of these results provide a novel link between the regulation of endothelial cell function and complement system activation, and they suggest that MASP-1-induced PAR4 activation could contribute to the development of the inflammatory reaction. The Journal of Immunology, 2009, 183: 3409-3416.