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

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.

Prohibitin Protects Against Cigarette Smoke Extract-Induced Cell Apoptosis in Cultured Human Pulmonary Microvascular Endothelial Cells

“…As demonstrated by our previous experiments, CSE treatment signi cantly triggered apoptotic cascade response in HPMECs [4]. By using ow cytometric quantitation of annexin V-propidium iodide staining, we found overexpression of prohibitin prevented apoptosis of HPMECs induced by CSE (Fig.…”

“…Studies conducted in our laboratory have revealed that CSE induce apoptosis in microvescular endothelial cells from lung [3,4]. CSE stimulation may generate ROS, induce DNA damage, leading to oxidative stress and subsequent endothelial cell apoptosis [5].…”

miRNA‐206 regulates human pulmonary microvascular endothelial cell apoptosis via targeting in chronic obstructive pulmonary disease

“…17 Notch3 is reported to play an important role in regulating the alveolar epithelium. Several of the key functional components in the Notch signaling are downregulated in smokers with COPD including Notch3.…”

Notch signaling in the mammalian respiratory system, specifically the trachea and lungs, in development, homeostasis, regeneration, and disease

“…The role of NOTCH in the progression of emphysema in COPD patients is not yet clear. A recent paper showed that NOTCH1/2/4 expression in endothelial cells was downregulated in COPD patients compared to healthy subjects (Zong et al., ). Given that the mouse Notch pathway plays a critical role in controlling apoptosis in endothelial cells (Limbourg et al., ), Notch signaling seems to be a promising key pathway for the progression of emphysema.…”

“…Given that the mouse Notch pathway plays a critical role in controlling apoptosis in endothelial cells (Limbourg et al., ), Notch signaling seems to be a promising key pathway for the progression of emphysema. The apoptosis of endothelial cells exposed to cigarette smoke extract was alleviated by Notch1 overexpression (Zong et al., ). These results suggest that the downregulation of NOTCH in endothelial cells increases their apoptosis, resulting in emphysema.…”