Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling
Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling
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DOI：
10.1074/jbc.m500747200
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发表时间：
2005-05-20
影响因子：
4.8
通讯作者：
Ruf, W
中科院分区：
文献类型：
--
作者：
Riewald, M;Ruf, W
活化蛋白C（APC）具有不依赖于抗凝的抗炎和血管保护作用。我们以前确定的原型凝血酶受体，蛋白酶激活受体-1（PAR 1），作为一种新的APC-内皮细胞蛋白C受体（EPCR）信号通路的一部分，在内皮细胞。在野生型和PAR 1（-/-）小鼠中的实验表明，静脉注射APC导致肺中PAR 1依赖性基因诱导。在严重脓毒症中，血管内皮发生了深刻的变化，这是APC的批准治疗适应症。与PAR 1类似，APC通过典型切割激活PAR 2。尽管PAR 2在尼古丁刺激的内皮细胞中上调，但APC信号仍然依赖PAR 1。大规模的基因表达谱记录显着的差异，在上调和下调基因之间的APC和凝血酶信号在精氨酸刺激的细胞。APC下调转录的促凋亡蛋白，包括p53和血小板反应蛋白-1，但p53是不变的，血小板反应蛋白甚至上调凝血酶。因此，通过相同的受体PAR 1、APC和凝血酶的信号传导，可以在扰动的内皮中发挥不同的生物学效应。这些数据可以解释APC如何通过EPCR-PAR 1信号传导而具有治疗保护作用，尽管由于弥散性血管内凝血病而持续产生凝血酶。
Activated protein C (APC) has anti-inflammatory and vascular protective effects independent of anticoagulation. We previously identified the prototypical thrombin receptor, protease-activated receptor-1 (PAR1), as part of a novel APC-endothelial cell protein C receptor ( EPCR) signaling pathway in endothelial cells. Experiments in wild-type and PAR1(-/-) mice demonstrated that intravenous injection of APC leads to PAR1-dependent gene induction in the lung. The vascular endothelium undergoes profound changes in severe sepsis, the approved therapeutic indication for APC. Similar to PAR1, APC activated PAR2 through canonical cleavage. Although PAR2 was up-regulated in cytokine-stimulated endothelial cells, APC signaling remained PAR1-dependent. Large scale gene expression profiling documented marked differences in both up- and down-regulated genes between APC and thrombin signaling in cytokine-stimulated cells. APC down-regulated transcripts for proapoptotic proteins including p53 and thrombospondin-1, but p53 was unchanged, and thrombospondin was even upregulated by thrombin. Concordant PAR1-dependent effects on protein levels were found. Thus, by signaling through the same receptor PAR1, APC, and thrombin can exert distinct biological effects in perturbed endothelium. These data may explain how APC can be therapeutically protective through the EPCR-PAR1 signaling despite ongoing thrombin generation due to disseminated intravascular coagulopathy.