Tissue factor (TF) is the principal initiator of blood coagulation and is necessary for thrombosis. We previously reported that lysophosphatidic acid (LPA), a potent bioactive lipid, highly induces TF expression at the transcriptional level in vascular smooth muscle cells. To date, however, the specific role of the LPA receptor is unknown, and the intracellular signaling pathways that lead to LPA induction of TF have been largely undetermined. In the current study, we found that LPA markedly induced protein kinase D (PKD) activation in mouse aortic smooth muscle cells (MASMCs). Small-interfering RNA-mediated knockdown of PKD2 blocked LPA-induced TF expression and activity, indicating that PKD2 is the key intracellular mediator of LPA signaling leading to the expression and cell surface activity of TF. Furthermore, our data reveal a novel finding that PKD2 mediates LPA-induced TF expression via the p38α and JNK2 MAPK signaling pathways, which are accompanied by the PKD-independent MEK1/2-ERK-JNK pathway. To identify the LPA receptor(s) responsible for LPA-induced TF expression, we isolated MASMCs from LPA receptor-knockout mice. Our results demonstrated that SMCs isolated from LPA receptor 1 (LPA1)-deficient mice completely lost responsiveness to LPA stimulation, which mediates induction of TF expression and activation of PKD and p38/JNK MAPK, indicating that LPA1 is responsible for PKD2-mediated activation of JNK2 and p38α. Taken together, our data reveal a new signaling mechanism in which the LPA1-PKD2 axis mediates LPA-induced TF expression via the p38α and JNK2 pathways. This finding provides new insights into LPA signaling, the PKD2 pathway, and the mechanisms of coagulation/atherothrombosis.

中文翻译：

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LPA1 介导的 PKD2 激活通过平滑肌细胞中的 p38α 和 JNK2 MAPK 通路促进 LPA 诱导的组织因子表达。

组织因子 (TF) 是凝血的主要引发剂，是血栓形成所必需的。我们之前报道过溶血磷脂酸 (LPA) 是一种有效的生物活性脂质，在血管平滑肌细胞的转录水平上高度诱导 TF 表达。然而，迄今为止，LPA 受体的具体作用尚不清楚，导致 LPA 诱导 TF 的细胞内信号通路在很大程度上尚未确定。在目前的研究中，我们发现 LPA 显着诱导小鼠主动脉平滑肌细胞 (MASMCs) 中的蛋白激酶 D (PKD) 活化。小干扰 RNA 介导的 PKD2 敲低阻断了 LPA 诱导的 TF 表达和活性，表明 PKD2 是导致 TF 表达和细胞表面活性的 LPA 信号传导的关键细胞内介质。此外，我们的数据揭示了一个新发现，即 PKD2 通过 p38α 和 JNK2 MAPK 信号通路介导 LPA 诱导的 TF 表达，这些信号通路伴随着 PKD 非依赖性 MEK1/2-ERK-JNK 通路。为了确定负责 LPA 诱导的 TF 表达的 LPA 受体，我们从 LPA 受体敲除小鼠中分离出 MASMC。我们的研究结果表明，从 LPA 受体 1 (LPA1) 缺陷小鼠中分离的 SMC 完全丧失了对 LPA 刺激的反应，LPA 刺激介导 TF 表达的诱导和 PKD 和 p38/JNK MAPK 的激活，表明 LPA1 负责 PKD2 介导的激活JNK2 和 p38α。总之，我们的数据揭示了一种新的信号机制，其中 LPA1-PKD2 轴通过 p38α 和 JNK2 途径介导 LPA 诱导的 TF 表达。这一发现为 LPA 信号传导、PKD2 通路、