Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells
Genetic evidence that protease-activated receptors mediate factor Xa signaling in endothelial cells
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DOI：
10.1074/jbc.m108555200
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发表时间：
2002-05-03
影响因子：
4.8
通讯作者：
Coughlin, SR
中科院分区：
文献类型：
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作者：
Camerer, E;Kataoka, H;Coughlin, SR
凝血蛋白酶因子Xa (Xa)(1)触发多种细胞反应，可能对组织损伤的炎症反应很重要。蛋白酶激活受体（PAR1， PAR2和PAR4）可以在异源表达系统中介导Xa信号。然而，其他候选Xa受体已经被描述，并且一个或多个PARs在相关分化细胞中的Xa信号传导程度尚不清楚。我们检测了野生型和par缺陷小鼠内皮细胞中的Xa信号。野生型内皮细胞对PAR1、PAR2和PAR4激动剂有反应。与野生型相比，xa触发的磷酸肌苷水解在Par2 -/-内皮细胞中减少了60-75%，在Par1 -/-内皮细胞中减少了20-30%，在PARI拮抗剂处理的Par2 -/-内皮细胞中减少了接近90%。当ERK1/2磷酸化用于评估Xa信号时，也得到了类似的结果。因此，在这些内皮细胞制备中，PAR2是主要的内源性Xa受体，并且PAR2和PAR1似乎共同占内皮Xa信号传导的90%。相比之下，在成纤维细胞中，PAR1本身几乎占了所有xa诱导的磷酸肌苷水解。这一信息对于敲除小鼠研究的设计和解释至关重要，以探索Xa信号在体内的可能作用。
The coagulation protease Factor Xa (Xa)(1) triggers a variety of cellular responses that may be important for inflammatory reactions to tissue injury. Protease-activated receptors (PAR1, PAR2, and PAR4) can mediate Xa signaling in heterologous expression systems. However, other candidate Xa receptors have been described, and the extent to which one or more PARs account for Xa signaling in relevant differentiated cells is unknown. We examined Xa signaling in endothelial cells from wildtype and PAR-deficient mice. Wild-type endothelial cells responded to agonists for PAR1, PAR2, and PAR4. Relative to wild-type, Xa-triggered phosphoinositide hydrolysis was reduced by 60-75% in Par2 -/- endothelial cells, by 20-30% in Par1 -/- endothelial cells, and by similar to90% in Par2 -/- endothelial cells treated with a PARI antagonist. Similar results were obtained when ERK1/2 phosphorylation was used to assess Xa signaling. Thus PAR2 is the main endogenous Xa receptor in these endothelial cell preparations and, together, PAR2 and PAR1 appear to account for similar to90% of endothelial Xa signaling. By contrast, in fibroblasts, PAR1 by itself accounted for virtually all Xa-induced phosphoinositide hydrolysis. This information is critical for the design and interpretation of knockout mouse studies to probe the possible roles of Xa signaling in vivo.