Resveratrol attenuates cigarette smoke induced endothelial apoptosis by activating Notch1 signaling mediated autophagy

Abstract Background Endothelial apoptosis contributes to the pathogenesis of chronic obstructive pulmonary disease (COPD). Our previous studies have validated Notch1 as an anti-apoptotic signaling in cigarette smoke (CS)-induced endothelial apoptosis. Resveratrol (RESV) is a naturally occurring polyphenol that exhibits an anti-apoptotic activity in endothelial cells that exposed to many kinds of destructive stimulus. However, the effects of resveratrol on Notch1 signaling in CS-induced endothelial apoptosis have not yet been fully elucidated. Therefore, the aim of this study was to examine whether RESV can protect endothelial cells from cigarette smoke induced apoptosis via regulating Notch1 signaling. Methods HUVECs were pretreated with RESV for 2 h, followed by cotreatment with 2.5%CSE for 24h to explore the role of RESV in CSE induced endothelial apoptosis. 3-MA or rapamycin was used to alter autophagic levels. Lentivirus Notch1 intracellular domain (LV-N1ICD) or γ-secretase inhibitor (DAPT) were used to change Notch1 expression. The expression of Notch1, autophagic and apoptotic markers were examined by Western blot and the apoptosis rate was detected by Flow cytometry analysis. Results Our results showed that activating autophagy reduced CSE-induced endothelial apoptosis, while blocking autophagy promoted cell apoptosis in HUVECs. RESV pretreatment attenuated the CSE-induced endothelial apoptosis and activated Notch1 signaling. RESV pretreatment also increased LC3b-II and Beclin1 production, decreased p62 and mTOR expression. 3-MA treatment inhibited autophagy and aggravated CSE induced apoptosis, while rapamycin promoted autophagy, led to a decrease in cell apoptosis. LV-N1ICD transfection upregulated autophagy and reduced apoptosis. However, this protective effect was abolished by 3-MA treatment. In cells treated with DAPT, autophagy was decreased, while apoptosis was increased. RESV partly rescued the DAPT induced apoptosis by activating Notch1 signaling. Conclusion In HUVECs, RESV attenuates CSE induced endothelial apoptosis by inducing autophagy in a Notch1-dependent manner.

Download Full-text

Resveratrol attenuates cigarette smoke induced endothelial apoptosis by activating Notch1 signaling mediated autophagy

10.21203/rs.3.rs-27268/v2 ◽

2020 ◽

Author(s):

Dandan Zong ◽

Xiang-ming Liu ◽

Jin-hua Li ◽

Ruo-yun Ouyang ◽

Ying-jiao Long ◽

...

Keyword(s):

Endothelial Cells ◽

Cigarette Smoke ◽

Cell Apoptosis ◽

Umbilical Vein ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Endothelial Apoptosis ◽

Notch1 Signaling ◽

Induced Apoptosis

Abstract Background Increasing evidences have showed that endothelial apoptosis contributes to cigarette smoke (CS)-induced disease progression, such as chronic obstructive pulmonary disease (COPD). Our previous studies have validated Notch1 as an anti-apoptotic signaling in cigarette smoke (CS)-induced endothelial apoptosis. Resveratrol (RESV) is a naturally occurring polyphenol that exhibits an anti-apoptotic activity in endothelial cells that exposed to many kinds of destructive stimulus. However, the effects of resveratrol on Notch1 signaling in CS-induced endothelial apoptosis have not yet been fully elucidated. Therefore, the aim of this study was to examine whether RESV can protect endothelial cells from cigarette smoke induced apoptosis via regulating Notch1 signaling. Methods Human umbilical vein endothelial cells (HUVECs) were pretreated with RESV for 2 h, followed by cotreatment with 2.5%CSE for 24h to explore the role of RESV in CSE induced endothelial apoptosis. 3-methyladenine (3-MA) or rapamycin was used to alter autophagic levels. Lentivirus Notch1 intracellular domain (LV-N1ICD) or γ-secretase inhibitor (DAPT) were used to change Notch1 expression. The expression of Notch1, autophagic and apoptotic markers were examined by Western blot and the apoptosis rate was detected by Flow cytometry analysis. Results Our results showed that activating autophagy reduced CSE-induced endothelial apoptosis, while blocking autophagy promoted cell apoptosis in HUVECs. RESV pretreatment attenuated the CSE-induced endothelial apoptosis and activated Notch1 signaling. RESV pretreatment also increased LC3b-II and Beclin1 production, decreased p62 and mTOR expression. 3-MA treatment inhibited autophagy and aggravated CSE induced apoptosis, while rapamycin promoted autophagy, led to a decrease in cell apoptosis. LV-N1ICD transfection upregulated autophagy and reduced apoptosis. However, this protective effect was abolished by 3-MA treatment. In cells treated with DAPT, autophagy was decreased, while apoptosis was increased. RESV partly rescued the DAPT induced apoptosis by activating Notch1 signaling. Conclusion In HUVECs, RESV attenuates CSE induced endothelial apoptosis by inducing autophagy in a Notch1-dependent manner.

Download Full-text

Resveratrol attenuates cigarette smoke induced endothelial apoptosis by activating Notch1 signaling mediated autophagy

Respiratory Research ◽

10.1186/s12931-021-01620-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Dan-dan Zong ◽

Xiang-ming Liu ◽

Jin-hua Li ◽

Ruo-yun Ouyang ◽

Ying-jiao Long ◽

...

Keyword(s):

Endothelial Cells ◽

Cigarette Smoke ◽

Cell Apoptosis ◽

Umbilical Vein ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Endothelial Apoptosis ◽

Notch1 Signaling ◽

Induced Apoptosis

Abstract Background Increasing evidence shows that endothelial apoptosis contributes to cigarette smoke (CS)-induced disease progression, such as chronic obstructive pulmonary disease (COPD). Our previous studies have validated Notch1 as an anti-apoptotic signaling in CS-induced endothelial apoptosis. Resveratrol (RESV) is a naturally occurring polyphenol that exhibits an anti-apoptotic activity in endothelial cells that exposed to many kinds of destructive stimulus. However, the effects of resveratrol on Notch1 signaling in CS-induced endothelial apoptosis have not yet been fully elucidated. Therefore, the aim of this study was to examine whether RESV can protect endothelial cells from CS-induced apoptosis via regulating Notch1 signaling. Methods Human umbilical vein endothelial cells (HUVECs) were pretreated with RESV for 2 h, followed by cotreatment with 2.5%CSE for 24 h to explore the role of RESV in CSE induced endothelial apoptosis. 3-methyladenine (3-MA) or rapamycin was used to alter autophagic levels. Lentivirus Notch1 intracellular domain (LV-N1ICD), γ-secretase inhibitor (DAPT) and Notch1 siRNA were used to change Notch1 expression. The expression of Notch1, autophagic and apoptotic markers were examined by Western blot and the apoptosis rate was detected by Flow cytometry analysis. Results Our results showed that activating autophagy reduced CSE-induced endothelial apoptosis, while blocking autophagy promoted cell apoptosis in HUVECs. RESV pretreatment attenuated the CSE-induced endothelial apoptosis and activated Notch1 signaling. RESV pretreatment also increased LC3b-II and Beclin1 production, decreased p62 and mTOR expression. 3-MA treatment inhibited autophagy and aggravated CSE induced apoptosis, while rapamycin promoted autophagy, led to a decrease in cell apoptosis. LV-N1ICD transfection upregulated autophagy and reduced apoptosis. However, this protective effect was abolished by 3-MA treatment. In cells treated with DAPT or Notch1 siRNA, autophagy was decreased, while apoptosis was increased. RESV partly rescued the DAPT or Notch1 siRNA induced apoptosis by activating Notch1 signaling. Conclusion In HUVECs, RESV attenuates CSE induced endothelial apoptosis by inducing autophagy in a Notch1-dependent manner.

Download Full-text

Resveratrol attenuates cigarette smoke induced endothelial apoptosis by activating Notch1 signaling mediated autophagy

10.21203/rs.3.rs-27268/v3 ◽

2020 ◽

Author(s):

Dandan Zong ◽

Xiang-ming Liu ◽

Jin-hua Li ◽

Ruo-yun Ouyang ◽

Ying-jiao Long ◽

...

Keyword(s):

Endothelial Cells ◽

Cigarette Smoke ◽

Cell Apoptosis ◽

Umbilical Vein ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Endothelial Apoptosis ◽

Notch1 Signaling ◽

Induced Apoptosis

Abstract Background: Increasing evidences have showed that endothelial apoptosis contributes to cigarette smoke (CS)-induced disease progression, such as chronic obstructive pulmonary disease (COPD). Our previous studies have validated Notch1 as an anti-apoptotic signaling in cigarette smoke (CS)-induced endothelial apoptosis. Resveratrol (RESV) is a naturally occurring polyphenol that exhibits an anti-apoptotic activity in endothelial cells that exposed to many kinds of destructive stimulus. However, the effects of resveratrol on Notch1 signaling in CS-induced endothelial apoptosis have not yet been fully elucidated. Therefore, the aim of this study was to examine whether RESV can protect endothelial cells from cigarette smoke induced apoptosis via regulating Notch1 signaling. Methods: Human umbilical vein endothelial cells (HUVECs) were pretreated with RESV for 2 h, followed by cotreatment with 2.5%CSE for 24h to explore the role of RESV in CSE induced endothelial apoptosis. 3-methyladenine (3-MA) or rapamycin was used to alter autophagic levels. Lentivirus Notch1 intracellular domain (LV-N1ICD) or γ-secretase inhibitor (DAPT) were used to change Notch1 expression. The expression of Notch1, autophagic and apoptotic markers were examined by Western blot and the apoptosis rate was detected by Flow cytometry analysis. Results: Our results showed that activating autophagy reduced CSE-induced endothelial apoptosis, while blocking autophagy promoted cell apoptosis in HUVECs. RESV pretreatment attenuated the CSE-induced endothelial apoptosis and activated Notch1 signaling. RESV pretreatment also increased LC3b-II and Beclin1 production, decreased p62 and mTOR expression. 3-MA treatment inhibited autophagy and aggravated CSE induced apoptosis, while rapamycin promoted autophagy, led to a decrease in cell apoptosis. LV-N1ICD transfection upregulated autophagy and reduced apoptosis. However, this protective effect was abolished by 3-MA treatment. In cells treated with DAPT, autophagy was decreased, while apoptosis was increased. RESV partly rescued the DAPT induced apoptosis by activating Notch1 signaling. Conclusion: In HUVECs, RESV attenuates CSE induced endothelial apoptosis by inducing autophagy in a Notch1-dependent manner.

Download Full-text

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

AJP Cell Physiology ◽

10.1152/ajpcell.00182.2017 ◽

2018 ◽

Vol 315 (3) ◽

pp. C330-C340 ◽

Cited By ~ 17

Author(s):

Dandan Zong ◽

Jinhua Li ◽

Shan Cai ◽

Shengdong He ◽

Qingqing Liu ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Endothelial Cells ◽

Notch Signaling ◽

Signaling Pathway ◽

Notch Signaling Pathway ◽

Chronic Obstructive ◽

Erk Pathway ◽

Obstructive Pulmonary Disease ◽

Endothelial Apoptosis ◽

Induced Apoptosis

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.

Download Full-text

Prohibitin protects against cigarette smoke extract-induced cell apoptosis in cultured human pulmonary microvascular endothelial cells

10.1101/2020.04.30.071589 ◽

2020 ◽

Author(s):

Yating Peng ◽

Zijing Zhou ◽

Aiyuan Zhou ◽

JiaXi Duan ◽

Hong Peng ◽

...

Keyword(s):

Endothelial Cells ◽

Cigarette Smoke ◽

Cell Apoptosis ◽

Cigarette Smoke Extract ◽

Microvascular Endothelial Cells ◽

Cigarette Smoke Exposure ◽

Dependent Manner ◽

Pulmonary Microvascular Endothelial Cells ◽

Mitochondrial Transcription Factor ◽

Microvascular Endothelial

Prohibitin is an evolutionarily conserved and ubiquitously expressed protein in eukaryocyte. It mediate many important roles in cell survival, apoptosis, autophagy and senescence. In the present study, we aimed to explore the role of prohibitin in cigarette smoke extract (CSE)-induced apoptosis of human pulmonary microvascular endothelial cells (HPMECs). For this purpose, HPMECs were trasfected with prohibitin and challenged with CSE. Our results showed that CSE exposure inhibited prohibitin expression in a dose-dependent manner in HPMECs. Overexpression of prohibitin could protect cell from CSE-induced injury by inhibiting CSE-induced cell apoptosis, inhibiting reactive oxygen species (ROS) production, increase mitochondrial membrane potential, increase the content of mitochondrial transcription factor A (mtTFA), IKKα/β phosphorylation and IκB-α degradation. CSE decreases prohibitin expression in endothelial cells and restoration of prohibitin expression in these cells can protect against the deleterious effects of CSE on mitochondrial and cells. We identified prohibitin is a novel regulator of endothelial cell apoptosis and survival in the context of cigarette smoke exposure.

Download Full-text

LncRNA-CCAT1/miR-152-5p is Involved in CSE-Induced Inflammation in HBE Cells Via Regulating ERK Signaling Pathway

10.21203/rs.3.rs-940217/v1 ◽

2021 ◽

Author(s):

Dan-dan Zong ◽

Xiang-ming Liu ◽

Jin-hua Li ◽

Ying-jiao Long ◽

Ruo-yun Ouyang ◽

...

Keyword(s):

Signaling Pathway ◽

Cigarette Smoke ◽

Specific Inhibitor ◽

Erk Signaling ◽

Luciferase Reporter ◽

Enzyme Linked Immunosorbent Assay ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Qrt Pcr

Abstract Background: Emerging studies have noted that dysregulated long non-coding RNAs (lncRNAs) are implicated in the pathological processes of chronic obstructive pulmonary disease (COPD). LncRNA colon cancer-associated transcript 1 (CCAT1) plays well-defined roles in the inflammatory progression. The study aims to figure out the effect and regulatory mechanism of CCAT1 in the cigarette smoke induced inflammation in COPD. Methods: The expression levels of CCAT1 and miR-152-3p were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The inflammatory levels of IL-1β and IL-6 were evaluated by qRT-PCR and enzyme-linked immunosorbent assay (ELISA). Western blot was used for the measurement of ERK1/2, p-ERK1/2 protein levels. Luciferase reporter assay was performed for the target gene analysis.Results: CCAT1 was highly expressed in lung tissues of smokers with COPD compared with non-smokers without COPD samples. In human bronchial epithelial (HBE) cells, cigarette smoke extract (CSE) treatment led to an increase in CCAT1 expression in a dose- and time- dependent manner. Functional experiments showed that knockdown of CCAT1 ameliorated CSE-induced inflammation. Mechanistically, CCAT1 directly targeted miR-152-3p, and miR-197-3p overexpression reversed the pro-inflammatory effects of CCAT1 on HBE cells. Subsequently, miR-152-3p was found to regulate ERK signaling pathway. PD98059, ERK specific inhibitor, reversed miR-152-3p inhibition mediated inflammation in HBE cells. In addition, CCAT1 acted as a sponge for miR-152-3p to positively regulate ERK signaling pathway. Conclusion: Current findings suggest that CCAT1 promoted inflammation by activating ERK signal pathway via sponging miR‑152‑3p in CSE‑treated HBE cells. These results may provide a novel therapeutic target for alleviating cigarette smoke mediated airway inflammation.

Download Full-text

Endothelial Progenitor Cells as Pathogenetic and Diagnostic Factors, and Potential Targets for GLP-1 in Combination with Metabolic Syndrome and Chronic Obstructive Pulmonary Disease

International Journal of Molecular Sciences ◽

10.3390/ijms20051105 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1105 ◽

Cited By ~ 3

Author(s):

Evgenii Skurikhin ◽

Olga Pershina ◽

Angelina Pakhomova ◽

Edgar Pan ◽

Vyacheslav Krupin ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Metabolic Syndrome ◽

Endothelial Cells ◽

Progenitor Cells ◽

Pulmonary Disease ◽

Endothelial Progenitor Cells ◽

Cigarette Smoke ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease

In clinical practice, there are patients with a combination of metabolic syndrome (MS) and chronic obstructive pulmonary disease (COPD). The pathological mechanisms linking MS and COPD are largely unknown. It remains unclear whether the effect of MS (possible obesity) has a major impact on the progression of COPD. This complicates the development of effective approaches for the treatment of patients with a diagnosis of MS and COPD. Experiments were performed on female C57BL/6 mice. Introduction of monosodium glutamate and extract of cigarette smoke was modeled to simulate the combined pathology of lipid disorders and emphysema. Biological effects of glucagon-like peptide 1 (GLP-1) and GLP-1 on endothelial progenitor cells (EPC) in vitro and in vivo were evaluated. Histological, immunohistochemical methods, biochemical methods, cytometric analysis of markers identifying EPC were used in the study. The CD31+ endothelial cells in vitro evaluation was produced by Flow Cytometry and Image Processing of each well with a Cytation™ 3. GLP-1 reduces the area of emphysema and increases the number of CD31+ endothelial cells in the lungs of mice in conditions of dyslipidemia and damage to alveolar tissue of cigarette smoke extract. The regenerative effects of GLP-1 are caused by a decrease in inflammation, a positive effect on lipid metabolism and glucose metabolism. EPC are proposed as pathogenetic and diagnostic markers of endothelial disorders in combination of MS with COPD. Based on GLP-1, it is proposed to create a drug to stimulate the regeneration of endothelium damaged in MS and COPD.

Download Full-text

Characterization of cigarette smoke-induced inflammatory and mucus hypersecretory changes in rat lung and the role of CXCR2 ligands in mediating this effect

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00317.2004 ◽

2005 ◽

Vol 288 (3) ◽

pp. L514-L522 ◽

Cited By ~ 61

Author(s):

Christopher S. Stevenson ◽

Kevin Coote ◽

Ruth Webster ◽

Helinor Johnston ◽

Hazel C. Atherton ◽

...

Keyword(s):

Cigarette Smoke ◽

Neutrophil Migration ◽

Neutrophil Infiltration ◽

Lavage Fluid ◽

Whole Body ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Rat Growth ◽

Inflammatory Changes

Repetitive, acute inflammatory insults elicited by cigarette smoke (CS) contribute to the development of chronic obstructive pulmonary disease (COPD), a disorder associated with lung inflammation and mucus hypersecretion. Presently, there is a poor understanding of the acute inflammatory mechanisms involved in this process. The aims of this study were to develop an acute model to investigate temporal inflammatory changes occurring after CS exposure. Rats were exposed to whole body CS (once daily) generated from filtered research cigarettes. Initial studies indicated the generation of a neutrophilic/mucus hypersecreting lung phenotype in <4 days. Subsequent studies demonstrated that just two exposures to CS (15 h apart) elicited a robust inflammatory/mucus hypersecretory phenotype that was used to investigate mechanisms driving this response. Cytokine-induced neutrophil chemoattractants (CINCs) 1–3, the rat growth-related oncogene-α family homologs, and IL-1β demonstrated time-dependent increases in lung tissue or lavage fluid over the 24-h period following CS exposure. The temporal changes in the neutrophil chemokines, CINCs 1–3, mirrored increases in neutrophil infiltration, indicative of a role in neutrophil migration. In addition, a specific CXCR2 antagonist, SB-332235, effectively inhibited CS-induced neutrophilia in a dose-dependent manner, supporting this conclusion. This modeling of the response of the rat airways to acute CS exposure indicates 1) as few as two exposures to CS will induce a phenotype with similarities to COPD and 2) a novel role for CINCs in the generation of this response. These observations represent a paradigm for the study of acute, repetitive lung insults that contribute to the development of chronic disease.

Download Full-text

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

10.21203/rs.3.rs-32653/v1 ◽

2020 ◽

Author(s):

Yating Peng ◽

Zijing Zhou ◽

Aiyuan Zhou ◽

JiaXi Duan ◽

Hong Peng ◽

...

Keyword(s):

Endothelial Cells ◽

Cigarette Smoke ◽

Cell Apoptosis ◽

Cigarette Smoke Extract ◽

Microvascular Endothelial Cells ◽

Cigarette Smoke Exposure ◽

Dependent Manner ◽

Pulmonary Microvascular Endothelial Cells ◽

Mitochondrial Transcription Factor ◽

Microvascular Endothelial

Abstract Prohibitin is an evolutionarily conserved and ubiquitously expressed protein in eukaryocyte. It mediate many important roles in cell survival, apoptosis, autophagy and senescence. In the present study, we aimed to explore the role of prohibitin in cigarette smoke extract (CSE)-induced apoptosis of human pulmonary microvascular endothelial cells (HPMECs). For this purpose, HPMECs were trasfected with prohibitin and challenged with CSE. Our results showed that CSE exposure inhibited prohibitin expression in a dose-dependent manner in HPMECs. Overexpression of prohibitin could protect cell from CSE-induced injury by inhibiting CSE-induced cell apoptosis, inhibiting reactive oxygen species (ROS) production, increase mitochondrial membrane potential, increase the content of mitochondrial transcription factor A (mtTFA), IKKα/β phosphorylation and IκB-α degradation. CSE decreases prohibitin expression in endothelial cells and restoration of prohibitin expression in these cells can protect against the deleterious effects of CSE on mitochondrial and cells. We identified prohibitin is a novel regulator of endothelial cell apoptosis and survival in the context of cigarette smoke exposure.

Download Full-text

LncRNA MIR155HG contributes to smoke-related chronic obstructive pulmonary disease by targeting miR-128-5p/BRD4 axis

Bioscience Reports ◽

10.1042/bsr20192567 ◽

2020 ◽

Vol 40 (3) ◽

Cited By ~ 1

Author(s):

Jie Song ◽

Qihu Wang ◽

Liguo Zong

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Macrophage Polarization ◽

Airway Disease ◽

Microvascular Endothelial Cell ◽

Chronic Obstructive ◽

Dependent Manner ◽

Obstructive Pulmonary Disease ◽

Apoptosis And Inflammation

Abstract Chronic obstructive pulmonary disease (COPD) is a common airway disease characterized by an exaggerated pulmonary inflammatory response. Long noncoding MIR155 host gene (lncRNA MIR155HG) has been identified to be related to the macrophage polarization in COPD. However, the detailed function of MIR155HG in cigarette smoke (CS)-mediated COPD remains largely unknown. The expression level of MIR155HG was elevated while miR-218-5p was decreased in lung tissues of smokers without or with COPD, especially in smokers with COPD, and cigarette smoke extract (CSE)-treated human pulmonary microvascular endothelial cell (HPMECs) in a dose- and time-dependent manner. Then, functional experiments showed that MIR155HG deletion could reverse CSE exposure-induced apoptosis and inflammation in HPMECs. MiR-218-5p was confirmed to be a target of MIR155HG and rescue assay showed miR-218-5p inhibitor attenuated the inhibitory action of MIR155HG knockdown on CSE-induced HPMECs. Subsequently, miR-218-5p was found to target bromodomain containing 4 (BRD4) directly, and miR-218-5p overexpression overturned CSE-induced injury of HPMECs via regulating BRD4. Additionally, co-expression analysis indicated MIR155HG indirectly regulated BRD4 expression in HPMECs via miR-218-5p. Thus, we concluded that MIR155HG contributed to the apoptosis and inflammation of HPMECs in smoke-related COPD by regulating miR-128-5p/BRD4 axis, providing a novel insight on the pathogenesis of COPD and a therapeutic strategy on COPD treatments.

Download Full-text