Long Noncoding RNA-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension
Long Noncoding RNA-Maternally Expressed Gene 3 Contributes to Hypoxic Pulmonary Hypertension
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长非编码 RNA 母体表达基因 3 导致缺氧性肺动脉高压
DOI：
10.1016/j.ymthe.2019.07.022
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发表时间：
2019-12-04
影响因子：
12.4
通讯作者：
Zhu, Daling
中科院分区：
文献类型：
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作者：
Xing, Yan;Zheng, Xiaodong;Zhu, Daling
长非编码RNA(LncRNAs)在缺氧性肺动脉高压(HPH)，特别是在肺动脉平滑肌细胞(PASMCs)增殖中的表达和作用目前尚不清楚。在此，我们检测了LncRNA母体表达基因3(LncRNA-MEG3)在HPH中的表达和作用。LncRNA-MEG3表达显著增加，主要定位于缺氧PASMCs的胞浆。肺组织特异性小干扰RNA(SiRNAs)抑制HPH的发生和发展。SiRNAs和Gapmer沉默LncRNA-MEG3可抑制体外培养的特发性肺动脉高压患者的PASMCs(IPAH-PASMCs)和低氧暴露的PASMCs的增殖和细胞周期进程。在机制上，我们发现lncRNA-MEG3与microRNA-328-3p(miR-3283p)相互作用并导致其降解，导致胰岛素样生长因子1受体(IGF1R)表达上调。IPAH-PASMCs及相应的HPH模型中，lncRNAMEG3、IGF1R高表达，miR-328-3p低表达。这些数据为lncRNA-MEG3在HPH中的贡献提供了见解。上调lncRNA-MEG3使细胞质miR-328-3p滞留，最终导致IGF1R的表达，揭示了lncRNA在低氧诱导的PASMC增殖中的调节机制。
The expression and function of long noncoding RNAs (lncRNAs) in the development of hypoxic pulmonary hypertension (HPH), especially in the proliferation of pulmonary artery smooth muscle cells (PASMCs), are largely unknown. Herein, we examined the expression and role of lncRNA-maternally expressed gene 3 (lncRNA-MEG3) in HPH. lncRNA-MEG3 was significantly increased and primarily localized in the cytoplasm of hypoxic PASMCs. lncRNA-MEG3 knockdown by lung-specific delivery of small interfering RNAs (siRNAs) significantly inhibited the development of HPH in vivo. Silencing of lncRNA-MEG3 by siRNAs and gapmers attenuated proliferation and cell-cycle progression in both PASMCs from idiopathic pulmonary arterial hypertension (iPAH) patients (iPAH-PASMCs) and hypoxia-exposed PASMCs in vitro. Mechanistically, we found that lncRNA-MEG3 interacts with and leads to the degradation of microRNA-328-3p (miR-3283p), leading to upregulation of insulin-like growth factor 1 receptor (IGF1R). Additionally, higher expression of lncRNAMEG3 and IGF1R and lower expression of miR-328-3p were observed in iPAH-PASMCs and relevant HPH models. These data provide insights into the contribution of lncRNA-MEG3 to HPH. Upregulation of lncRNA-MEG3 sequesters cytoplasmic miR-328-3p, eventually leading to expression of IGF1R, revealing a regulatory mechanism by lncRNAs in hypoxia-induced PASMC proliferation.