Division of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
Research Unit of Respiratory Disease, Central South University, Changsha, Hunan, 410011, China.
Respir Res. 2018 Jan 26;19(1):21. doi: 10.1186/s12931-018-0722-2.
Abnormal apoptosis of lung endothelial cells has been observed in emphysematous lung tissue and has been suggested to be an important upstream event in the pathogenesis of chronic obstructive pulmonary disease (COPD). Studies have shown that microRNAs (miRNAs) contribute to the pathogenesis of pulmonary diseases by regulating cell apoptosis. The present study was designed to investigate the expression of microRNA-34a (miR-34a) in human pulmonary microvascular endothelial cells (HPMECs) exposed to cigarette smoke extract (CSE), and the potential regulatory role of miR-34a in endothelial cell apoptosis.
Our results showed that the expression of miR-34a was significantly increased in CSE-treated HPMECs, and inhibiting miR-34a attenuated CSE-induced HPMEC apoptosis. Furthermore, expression of Notch-1, a receptor protein in the Notch signalling pathway, was decreased and was inversely correlated with miR-34a expression in HPMECs treated with CSE. Computational miRNA target prediction confirmed that Notch-1 is a target of miR-34a. Luciferase reporter assay further confirmed the direct interaction between miR-34a and the 3'-untranslated region (UTR) of Notch-1. Restoration of Notch-1 pathway was able to partially block the effect of miR-34a on HPMEC apoptosis. These results indicate that Notch-1 is a critical downstream target of miR-34a in regulating the CSE-induced HPMEC apoptosis.
Our results suggest that miR-34a plays a key role in CSE-induced endothelial cell apoptosis by directly regulating its target gene Notch-1 in endothelial cells.
在肺气肿肺组织中观察到肺内皮细胞的异常凋亡，并认为这是慢性阻塞性肺疾病（COPD）发病机制中的一个重要上游事件。研究表明，microRNAs（miRNAs）通过调节细胞凋亡参与肺部疾病的发病机制。本研究旨在探讨人肺微血管内皮细胞（HPMEC）暴露于香烟烟雾提取物（CSE）后 microRNA-34a（miR-34a）的表达情况，以及 miR-34a 在内皮细胞凋亡中的潜在调节作用。
我们的结果表明，CSE 处理的 HPMEC 中 miR-34a 的表达显著增加，抑制 miR-34a 可减轻 CSE 诱导的 HPMEC 凋亡。此外，在 CSE 处理的 HPMEC 中，Notch-1 表达降低，与 miR-34a 表达呈负相关，Notch-1 是 Notch 信号通路中的一种受体蛋白。计算 miRNA 靶标预测证实 Notch-1 是 miR-34a 的靶标。荧光素酶报告基因检测进一步证实了 miR-34a 与 Notch-1 的 3'-非翻译区（UTR）之间的直接相互作用。Notch-1 通路的恢复能够部分阻断 miR-34a 对 HPMEC 凋亡的影响。这些结果表明，Notch-1 是 miR-34a 调节 CSE 诱导的 HPMEC 凋亡的关键下游靶标。
我们的研究结果表明，miR-34a 通过直接调节内皮细胞中其靶基因 Notch-1，在 CSE 诱导的内皮细胞凋亡中发挥关键作用。
