Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells
Protease-activated receptors 1 and 4 mediate thrombin signaling in endothelial cells
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DOI：
10.1182/blood-2003-04-1130
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发表时间：
2003-11-01
期刊：
影响因子：
20.3
通讯作者：
Coughlin, SR
中科院分区：
文献类型：
--
作者：
Kataoka, H;Hamilton, JR;Coughlin, SR
定义相对重要性的蛋白酶激活受体（PARs）的凝血酶信号在小鼠内皮细胞中是至关重要的凝血酶信号在这些细胞中的基本理解和合理使用基因敲除小鼠探测凝血酶的作用在体内内皮细胞。我们研究了凝血酶和PAR激动剂诱导的野生型和PAR缺陷小鼠内皮细胞胞浆钙、磷酸肌醇水解、细胞外信号调节激酶（ERK）磷酸化和基因表达的增加。PAR 1和PAR 4激动剂分别在野生型内皮细胞中引发反应，但在Par 1（-/-）和Par 4（-/-）内皮细胞中不引发反应。钙成像证实，相当大一部分的个别内皮细胞对这两种激动剂作出反应。与野生型细胞相比，PAR 1（-/-）内皮细胞对低浓度凝血酶的反应明显降低，而缺乏PAR 1和PAR 4的细胞对高浓度凝血酶也没有反应。当新鲜分离的小鼠主动脉的内皮依赖性血管舒张被用作天然内皮细胞中信号传导的指标时，获得了类似的结果。因此，PAR 1是小鼠内皮细胞中的主要凝血酶受体，但PAR 4也有贡献。这些受体在体外和体内的内皮细胞中至少部分地起冗余作用，并且一起对于测量的凝血酶反应是必需的。(C)2003年，美国血液学会。
Defining the relative importance of protease-activated receptors (PARs) for thrombin signaling in mouse endothelial cells is critical for a basic understanding of thrombin signaling in these cells and for the rational use of knockout mice to probe the roles of thrombin's actions on endothelial cells in vivo. We examined thrombin- and PAR agonist-induced increases in cytoplasmic calcium, phosphoinositide hydrolysis, extracellular signal-regulated kinase (ERK) phosphorylation, and gene expression in endothelial cells from wild-type and PAR-deficient mice. PAR1 and PAR4 agonists triggered responses in wild-type but not in Par1(-/-) and Par4(-/-) endothelial cells, respectively. Calcium imaging confirmed that a substantial fraction of individual endothelial cells responded to both agonists. Compared with wild-type cells, Par1(-/-) endothelial cells showed markedly decreased responses to low concentrations of thrombin, and cells that lacked both PAR1 and PAR4 showed no responses to even high concentrations of thrombin. Similar results were obtained when endothelial-dependent vasorelaxation of freshly isolated mouse aorta was used as an index of signaling in native endothelial cells. Thus PAR1 is the major thrombin receptor in mouse endothelial cells, but PAR4 also contributes. These receptors serve at least partially redundant roles in endothelial cells in vitro and in vivo and together are necessary for the thrombin responses measured. (C) 2003 by The American Society of Hematology.