Induction of MicroRNA-221 by Platelet-derived Growth Factor Signaling Is Critical for Modulation of Vascular Smooth Muscle Phenotype
Induction of MicroRNA-221 by Platelet-derived Growth Factor Signaling Is Critical for Modulation of Vascular Smooth Muscle Phenotype
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DOI：
10.1074/jbc.m808788200
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发表时间：
2009-02-06
影响因子：
4.8
通讯作者：
Hata, Akiko
中科院分区：
文献类型：
--
作者：
Davis, Brandi N.;Hilyard, Aaron C.;Hata, Akiko
血小板衍生生长因子（PDGF）信号通路是动物发育和体内平衡的关键调节因子。PDGF通路的激活导致对动脉损伤的新生内膜增殖反应;它通过抑制SMC特异性基因表达和增加增殖和迁移速率来促进血管平滑肌细胞（vSMC）向收缩性较低的表型的转变。PDGF的这些多效性作用的分子机制尚未完全描述。在这里，我们确定了microRNA-221（miR-221），一种小的非编码RNA，作为vSMC响应PDGF信号传导的表型变化的调节剂。我们证明，miR-221在原代vSMC中经PDGF处理后被转录诱导，导致靶点c-Kit和p27 Kip 1下调。miR-221下调p27 Kip 1对于PDGF介导的细胞增殖诱导至关重要。此外，c-Kit减少通过减少肌心蛋白（Myocd）（一种有效的SMC特异性核辅激活因子）的表达，抑制SMC特异性收缩基因转录。我们的研究表明，PDGF信号，通过调节miR-221的表达，调节vSMC表型的两个关键决定因素，他们是SMC基因表达和细胞增殖。
The platelet-derived growth factor (PDGF) signaling pathway is a critical regulator of animal development and homeostasis. Activation of the PDGF pathway leads to neointimal proliferative responses to artery injury; it promotes a switch of vascular smooth muscle cells (vSMC) to a less contractile phenotype by inhibiting the SMC-specific gene expression and increasing the rate of proliferation and migration. The molecular mechanism for these pleiotropic effects of PDGFs has not been fully described. Here, we identify the microRNA-221 (miR-221), a small noncoding RNA, as a modulator of the phenotypic change of vSMCs in response to PDGF signaling. We demonstrate that miR-221 is transcriptionally induced upon PDGF treatment in primary vSMCs, leading to down-regulation of the targets c-Kit and p27Kip1. Down-regulation of p27Kip1 by miR-221 is critical for PDGF-mediated induction of cell proliferation. Additionally, decreased c-Kit causes inhibition of SMC-specific contractile gene transcription by reducing the expression of Myocardin (Myocd), a potent SMC-specific nuclear coactivator. Our study demonstrates that PDGF signaling, by modulating the expression of miR-221, regulates two critical determinants of the vSMC phenotype; they are SMC gene expression and cell proliferation.