Department of Respiratory Medicine, the Second Xiangya Hospital, Research Unit of Respiratory Disease, Diagnosis and Treatment Center of Respiratory Disease, Central South University , Changsha , China.
Department of Respiratory Medicine, Affiliated Hospital of Luzhou Medical College, Luzhou, China.
Am J Physiol Cell Physiol. 2018 Sep 1;315(3):C330-C340. doi: 10.1152/ajpcell.00182.2017. Epub 2018 Jun 6.
The Notch signaling pathway plays critical role for determining cell fate by controlling proliferation, differentiation, and apoptosis. In the current study, we investigated the roles of the Notch signaling pathway in cigarette smoke (CS)-induced endothelial apoptosis in chronic obstructive pulmonary disease (COPD). We obtained surgical specimens from 10 patients with COPD and 10 control participants. Notch1, 2, and 4 express in endothelial cells, whereas Notch3 mainly localizes in smooth muscle cells. Compared with control groups, we found that the expression of Notch1, 3, and 4 decreased, as well as their target genes Hes1 and Hes2, while the expression of Notch2 and extracellular signal-regulated kinase (ERK)1/2 increased in COPD patients compared with controls, as well as in human pulmonary microvascular endothelial cells (HPMECs) when exposed to CS extract (CSE). Overexpression of Notch1 with N1ICD in HPMECs markedly alleviated the cell apoptosis induced by CSE. The ERK signaling pathway was significantly activated by CSE, which correlated with CSE-induced apoptosis. However, this activation can be abolished by N1ICD overexpression. Furthermore, treatment of PD98059 (ERK inhibitor) significantly alleviated CSE-induced apoptosis, as well as reduced the methylation of mitochondrial transcription factor A (mtTFA) promoter, which was correlated with CS-induced endothelial apoptosis. These results suggest that CS alters Notch signaling in pulmonary endothelial cells. Notch1 protects against CS-induced endothelial apoptosis in COPD through inhibiting the ERK pathway, while the ERK pathway further regulates the methylation of mtTFA promotor.
Notch 信号通路通过控制细胞增殖、分化和凋亡，对细胞命运的决定起着至关重要的作用。在本研究中，我们探讨了 Notch 信号通路在香烟烟雾（CS）诱导的慢性阻塞性肺疾病（COPD）内皮细胞凋亡中的作用。我们从 10 例 COPD 患者和 10 例对照患者中获取手术标本。Notch1、2 和 4 在血管内皮细胞中表达，而 Notch3 主要定位于平滑肌细胞。与对照组相比，我们发现 COPD 患者中 Notch1、3 和 4 的表达以及其靶基因 Hes1 和 Hes2 的表达降低，而 Notch2 和细胞外信号调节激酶（ERK）1/2 的表达增加，并且当人肺微血管内皮细胞（HPMEC）暴露于香烟烟雾提取物（CSE）时也观察到类似的结果。在 HPMEC 中转染 Notch1 过表达载体（N1ICD）可明显减轻 CSE 诱导的细胞凋亡。CSE 显著激活了 ERK 信号通路，与 CSE 诱导的细胞凋亡相关。然而，这种激活可以被 N1ICD 过表达所抑制。此外，ERK 抑制剂 PD98059 的处理可显著减轻 CSE 诱导的细胞凋亡，并降低线粒体转录因子 A（mtTFA）启动子的甲基化水平，这与 CS 诱导的内皮细胞凋亡相关。这些结果表明 CS 改变了肺内皮细胞中的 Notch 信号。Notch1 通过抑制 ERK 通路来保护 COPD 内皮细胞免受 CS 诱导的凋亡，而 ERK 通路进一步调节 mtTFA 启动子的甲基化。
