MicroRNA-124 Suppresses the Transactivation of Nuclear Factor of Activated T Cells by Targeting Multiple Genes and Inhibits the Proliferation of Pulmonary Artery Smooth Muscle Cells
MicroRNA-124 Suppresses the Transactivation of Nuclear Factor of Activated T Cells by Targeting Multiple Genes and Inhibits the Proliferation of Pulmonary Artery Smooth Muscle Cells
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MicroRNA-124通过靶向多基因抑制活化T细胞核因子反式激活并抑制肺动脉平滑肌细胞增殖
DOI：
10.1074/jbc.m113.460287
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发表时间：
2013-08-30
影响因子：
4.8
通讯作者：
Liu, Lin
中科院分区：
文献类型：
--
作者：
Kang, Kang;Peng, Xiao;Liu, Lin
肺动脉平滑肌细胞（PASMC）的异常增殖和表型调节有助于许多心血管疾病的发病机制，包括肺动脉高压（PAH）。活化T细胞核因子（NFAT）信号通路与PASMC增殖和PAH相关。microRNAs（miRNAs）是一类在多种生物过程中发挥作用的小分子非编码RNA。为了系统地鉴定调节NFAT途径的特异性miRNA，将人初级miRNA文库应用于使用NFAT荧光素酶报告系统的基于细胞的高通量筛选。发现八种miRNA有效地调节NFAT活性。其中，miR-124强烈抑制NFAT报告基因活性，并降低NFAT的去磷酸化和核转位。miR-124还抑制Jurkat T细胞中IL-2的NFAT依赖性转录。miR-124通过靶向多个基因发挥作用，包括NFAT途径的已知组分NFATc 1和NFAT信号传导的两个新调节因子CAMTA 1（钙调蛋白结合转录激活因子1）和PTBP 1（多聚嘧啶片段结合蛋白1）。在生理学上，miR-124在人PASMC中被缺氧下调，与在此过程中NFAT的激活一致。在3周低氧处理的小鼠肺中也观察到miR-124的下调。此外，miR-124的过表达不仅抑制人PASMC增殖，而且通过抑制NFAT途径维持其分化表型。综上所述，我们的数据提供了miR-124作为NFAT通路抑制剂的第一个证据。低氧处理的PASMC中miR-124的下调及其抗增殖和促分化作用意味着miR-124在PAH治疗中的潜在价值。
Abnormal proliferation and phenotypic modulation of pulmonary artery smooth muscle cells (PASMC) contributes to the pathogenesis of numerous cardiovascular disorders, including pulmonary arterial hypertension (PAH). The nuclear factor of activated T cells (NFAT) signaling pathway is linked to PASMC proliferation and PAH. MicroRNAs (miRNAs) are small non-coding RNAs that function in diverse biological processes. To systemically identify the specific miRNAs that regulate the NFAT pathway, a human primary miRNA library was applied for cell-based high throughput screening with the NFAT luciferase reporter system. Eight miRNAs were found to modulate NFAT activity efficiently. Of them, miR-124 robustly inhibited NFAT reporter activity and decreased both the dephosphorylation and the nuclear translocation of NFAT. miR-124 also inhibited NFAT-dependent transcription of IL-2 in Jurkat T cells. miR-124 exerted its effects by targeting multiple genes, including a known component of the NFAT pathway, NFATc1, and two new regulators of NFAT signaling, CAMTA1 (calmodulin-binding transcription activator 1) and PTBP1 (polypyrimidine tract-binding protein 1). Physiologically, miR-124 was down-regulated by hypoxia in human PASMC, consistent with the activation of NFAT during this process. Down-regulation of miR-124 was also observed in 3-week hypoxia-treated mouse lungs. Furthermore, the overexpression of miR-124 not only inhibited human PASMC proliferation but also maintained its differentiated phenotype by repressing the NFAT pathway. Taken together, our data provide the first evidence that miR-124 acts as an inhibitor of the NFAT pathway. Down-regulation of miR-124 in hypoxia-treated PASMC and its antiproliferative and prodifferentiation effects imply a potential value for miR124 in the treatment of PAH.