Notch1 regulates endothelial apoptosis via the ERK pathway in chronic obstructive pulmonary disease.

Dandan Zong,Qingqing Liu,Shanshan Chen,Yan Chen,Ping Chen,Jinhua Li,Shengdong He,Shan Cai,Jiehan Jiang,Ruoyun Ouyang,Yingjiao Long

doi:10.1152/ajpcell.00182.2017

Abstract

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.

Highlights

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease characterized by a progressive and irrevers-ible airflow obstruction and destruction of parenchyma, which is mainly caused by cigarette smoke (CS) [32]
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)
Notch1 protects against CS-induced endothelial apoptosis in COPD through inhibiting the ERK pathway, while the ERK pathway further regulates the methylation of mitochondrial transcription factor A (mtTFA) promotor

Summary

Introduction

Ible airflow obstruction and destruction of parenchyma, which is mainly caused by cigarette smoke (CS) [32] This disease is a major public health burden and is the third leading cause of mortality worldwide [25]. Recent data suggested that abnormal apoptosis serves as a significant factor contributing to the destruction of pulmonary tissue in COPD [28]. Studies from both animal model and human confirmed that endothelial apoptosis plays an important role in the pathogenesis of emphysema and COPD [4, 14, 26, 36, 37]. The mechanism underlying the regulation of Notch signaling on endothelial apoptosis in COPD remains largely unknown

Methods

Results

Conclusion