Activation of Notch3 promotes pulmonary arterial smooth muscle cells proliferation via Hes1/p27Kip1 signaling pathway.
Activation of Notch3 promotes pulmonary arterial smooth muscle cells proliferation via Hes1/p27Kip1 signaling pathway.
复制标题
Notch3 的激活通过 Hes1/p27Kip1 信号通路促进肺动脉平滑肌细胞增殖。
DOI：
10.1016/j.fob.2015.08.007
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发表时间：
2015
期刊：
影响因子：
2.6
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Song Y;Zhang Y;Jiang H;Zhu Y;Liu L;Feng W;Yang L;Wang Y;Li M
NOTCH3受体(NICD3)过表达可诱导肺动脉平滑肌细胞(PASMC)增殖。NICD3上调Hes1的表达，下调p27Kip1的表达。HES1介导NICD3诱导的PASMCs p27Kip1减少和增殖。Notch3级联的激活通过刺激血管平滑肌细胞的增殖参与了肺动脉高压的发生发展。然而，这种效应背后的详细分子机制仍不清楚。本研究旨在解决这一问题。我们证明，腺病毒过表达Notch3受体胞内区(NICD3)可显著诱导原代培养的肺动脉平滑肌细胞增殖。伴随着Hes1蛋白的上调和p27Kip1蛋白的下调。更重要的是，我们观察到预先用siRNA沉默Hes1可以阻止NICD3过表达诱导的p27Kip1减少和细胞增殖。本研究提示，Hes1位于NICD3下游，通过下调p27Kip1的表达，特异性地介导Notch3信号诱导的肺动脉平滑肌细胞增殖。
Notch3 receptor (NICD3) over-expression induces proliferation of pulmonary arterial smooth muscle cells (PASMCs). NICD3 up-regulates Hes1 expression and reduces p27Kip1 expression. Hes1 mediates NICD3-induced p27Kip1 reduction and proliferation of PASMCs. Activation of the Notch3 cascade is involved in the development of pulmonary arterial hypertension by stimulating the proliferation of vascular smooth muscle cells. However, the detailed molecular mechanisms underlying this effect are still unclear. The present study aims to address this issue. We demonstrated that over-expression of intracellular domain of the Notch3 receptor (NICD3) by adenovirus transfection dramatically induced proliferation of primary cultured pulmonary artery smooth muscle cells. This was accompanied with up-regulation of Hes1 protein and down-regulation of p27Kip1 protein. More importantly, we observed that prior silencing of Hes1 with siRNA blocked NICD3 over-expression-induced p27Kip1 reduction and cell proliferation. The present study suggests that Hes1 lies downstream of NICD3 and particularly mediates Notch3 signaling-induced proliferation of pulmonary arterial smooth muscle cells by down-regulation of p27Kip1 expression.