Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway
Nur77 Suppresses Pulmonary Artery Smooth Muscle Cell Proliferation through Inhibition of the STAT3/Pim-1/NFAT Pathway
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DOI：
10.1165/rcmb.2013-0198oc
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发表时间：
2014-02-01
影响因子：
6.4
通讯作者：
Sun, Jianxin
中科院分区：
文献类型：
--
作者：
Liu, Yan;Zhang, Jian;Sun, Jianxin
孤儿核受体4A（NR 4A）家族在心血管系统细胞增殖、分化和存活的调节中起关键作用。然而，NR 4A受体表达调控的分子机制及其在肺动脉平滑肌细胞（PASMC）功能中的作用尚不清楚。在这里，我们研究了NR 4A家族是否调节PASMC增殖，如果是，涉及哪些机制。实时荧光定量RT-PCR结果显示，与NOR-1和Nurr 1相比，孤儿核受体Nur 77是NR 4A家族在大鼠PASMCs中表达量最高的成员。在大鼠PASMCs中，Nur 77的表达在肺动脉高压（PAH）的几种病理刺激，如缺氧，5-羟色胺（5-HT），血小板源性生长因子，内皮素-1强烈诱导。重要的是，Nur 77在野百合碱诱导的PAH大鼠的肺中也显著增加。此外，我们证明，5-HT显着上调Nur 77的表达，通过丝裂原活化蛋白激酶/细胞外信号调节激酶1/2途径。Nur 77过表达抑制5-HT诱导的PASMC增殖，以及细胞周期蛋白D1和增殖细胞核抗原的表达。从机制上讲，我们证明Nur 77特异性地与信号转导子和转录激活子3相互作用，从而抑制其磷酸化及其靶基因的表达，如Pim-1、活化T细胞核因子c2和PASMCs中的生存素。这些结果表明Nur 77是通过抑制活化T细胞轴的信号转导和转录激活因子3/Pim-1/核因子来调节PASMC增殖的新型负反馈调节剂。调节Nur 77活性可能代表了治疗PAH的一种新的治疗策略。
The orphan nuclear receptor 4A (NR4A) family plays critical roles in the regulation of cell proliferation, differentiation, and survival in the cardiovascular system. However, the molecular mechanisms underlying the regulation of NR4A receptor expression and its role in pulmonary artery smooth muscle cell (PASMC) function remain unclear. Here, we investigated whether the NR4A family regulates PASMC proliferation, and if so, which mechanisms are involved. By using quantitative real-time RT-PCR, we showed that the orphan nuclear receptor Nur77 was the most abundant member of NR4A family expressed in rat PASMCs, as compared with the two other members, NOR-1 and Nurr1. In rat PASMCs, expression of Nur77 was robustly induced in response to several pathologic stimuli of pulmonary arterial hypertension (PAH), such as hypoxia, 5-hydroxytryptamine (5-HT), platelet-derived growth factor, and endothelin-1. Importantly, Nur77 was also significantly increased in lungs of rats with monocrotaline-induced PAH. Furthermore, we demonstrated that 5-HT markedly up-regulated Nur77 expression through the mitogen-activated protein kinases/extracellular signal-regulated kinase 1/2 pathway. Overexpression of Nur77 inhibited 5-HT-induced PASMC proliferation, as well as the expression of cyclin D1 and proliferating cell nuclear antigen. Mechanistically, we demonstrated that Nur77 specifically interacts with signal transducer and activator of transcription 3, thus inhibiting its phosphorylation and expression of its target genes, such as Pim-1, nuclear factor of activated T cells c2, and survivin in PASMCs. These results indicate that Nur77 is a novel negative-feedback regulator of PASMC proliferation through inhibition of the signal transducer and activator of transcription 3/Pim-1/nuclear factor of activated T cells axis. Modulation of Nur77 activity may potentially represent a novel therapeutic strategy for the treatment of PAH.