MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition by targeting Myc in pulmonary arterial smooth muscle cells
MiR-449a-5p mediates mitochondrial dysfunction and phenotypic transition by targeting Myc in pulmonary arterial smooth muscle cells
复制标题
MiR-449a-5p 通过靶向肺动脉平滑肌细胞中的 Myc 介导线粒体功能障碍和表型转变
DOI：
10.1007/s00109-019-01751-7
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发表时间：
2019
影响因子：
4.7
通讯作者：
Zhu Daling
中科院分区：
文献类型：
--
作者：
Zhang Chen;Ma Cui;Zhang Lixin;Zhang Linlin;Zhang Fengying;Ma Mingfei;Zheng Xiaodong;Mao Min;Shen Tingting;Zhu Daling
摘要MicroRNAs被认为参与了肺动脉高压(PAH)，并调节了肺血管系统中的多种疾病途径。然而，其在病理中的分子作用尚未完全被发现，特别是在能量代谢和血管平滑肌细胞表型调节方面。在全基因组的miRNA测序分析中，发现了几个突变的miRNAs，其中miR-449a-5p可能是缺氧性PAH的候选基因，并证实了这种下降的趋势。此外，我们还发现miR-449a-5p在线粒体代谢障碍和肺动脉平滑肌细胞表型转化中起关键作用。随后，我们启动了转录因子Myc，该转录因子受miR-449a-5p的负调控，导致了参与肺动脉平滑肌细胞增殖的异常效应。综上所述，我们证明miR-449a-5p/Myc轴在PAH的发生发展中是不可或缺的。这些结果可能对理解和治疗PAH有重要意义。关键信息·在PAH-PAS和缺氧性PASMC中都存在miR-449a-5p的下调。·MIR-449a-5p参与缺氧诱导的PASMC线粒体功能障碍。·MIR-449a-5p抑制缺氧性PASMC的表型转换和增殖。·MIR-449a-5p的异常作用依赖于下游转录因子Myc。·Myc参与了PAH线粒体功能障碍和表型转换。
AbstractMicroRNAs have been considered to participate in pulmonary arterial hypertension (PAH) and regulate numerous disease pathways in pulmonary vasculature. However, the molecular role in the pathologies has not yet been fully uncovered, particularly in the view of energy metabolism and vascular smooth muscle cell phenotypic regulation. Here, several altered miRNAs are founded in genome-wide miRNA sequencing analysis, in which miR-449a-5p was identified as a probable candidate in hypoxic PAH and verified such a decreasing trend. Moreover, we identify that miR-449a-5p plays critical role in both mitochondria metabolic dysfunction and phenotype transformation of pulmonary arterial smooth muscle cells. Subsequently, we initiate that the transcription factor Myc, which is negatively regulated by miR-449a-5p, results in the aberrant effects contributing to pulmonary arterial smooth muscle cell proliferation. Taken together, we demonstrated that the miR-449a-5p/Myc axis is indispensable for the development and progression of PAH. These results may serve as a significant implication for understanding and treatment of PAH.Key messages• The downregulation of miR-449a-5p occurs in both PAH-PAs and hypoxic PASMCs.• MiR-449a-5p is involved in hypoxia-induced mitochondria dysfunction of PASMCs.• MiR-449a-5p inhibits hypoxic phenotypic transition and proliferation of PASMCs.• The aberrant effects of MiR-449a-5p depend on downstream transcription factor Myc.• Myc contributes to mitochondria dysfunction and phenotype transformation in PAH.