Oxidative stress mediates the apoptosis and epigenetic modification of the Bcl-2 promoter via DNMT1 in a cigarette smoke-induced emphysema model.
Aged
Animals
Apoptosis
/ physiology
Cigarette Smoking
/ adverse effects
DNA (Cytosine-5-)-Methyltransferase 1
/ genetics
Emphysema
/ etiology
Epigenesis, Genetic
/ physiology
Female
Humans
Inhalation Exposure
/ adverse effects
Lung
/ metabolism
Male
Mice
Mice, Inbred C57BL
Middle Aged
Oxidative Stress
/ physiology
Promoter Regions, Genetic
/ physiology
Proto-Oncogene Proteins c-bcl-2
/ genetics
Apoptosis
Bcl-2
DNMT1
Hypermethylation
Oxidative stress
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
03 Sep 2020
03 Sep 2020
Historique:
received:
30
04
2020
accepted:
24
08
2020
entrez:
5
9
2020
pubmed:
5
9
2020
medline:
11
8
2021
Statut:
epublish
Résumé
Emphysema is a crucial pathological characteristic of chronic obstructive pulmonary disease (COPD). Oxidative stress, apoptosis and epigenetic mechanisms contribute to the pathogenesis of emphysema. However, an attempt to accurately identify whether these mechanisms interact with each other and how they are triggered has never been conducted. The total reactive oxygen species (ROS) level, pulmonary apoptosis and B-cell lymphoma/leukemia-2 (Bcl-2) expression, an apoptosis regulator, were detected in samples from COPD patients. Bisulfite sequencing PCR (BSP) was conducted to observe the alterations in the methylation of the Bcl-2 promoter in specimens. The dysregulation of DNA methyltransferase enzyme 1 (DNMT1), a vital DNA methyltransferase enzyme, in the lungs of patients was confirmed through western blotting. To find out interactions between oxidative stress and DNA methylation in emphysema, mouse models were built with antioxidant treatment and DNMT1 silencing, and were examined with the pulmonary apoptosis, Bcl-2 and DNMT1 levels, and epigenetic alterations of Bcl-2. Higher ROS levels and pulmonary apoptosis were observed in COPD patients than in healthy controls. Downregulated Bcl-2 expression with increased promoter methylation and DNMT1 protein expression was found in COPD patients. Antioxidant treatment reduced the level of ROS, DNMT1 protein and emphysematous progression in the smoking models. Following DNMT1 blockade, smoking models showed improved lung function, pulmonary apoptosis, emphysematous progression, and increased Bcl-2 protein level with less promoter methylation than emphysema mice. Cigarette-induced oxidative stress mediates pulmonary apoptosis and hypermethylation of the Bcl-2 promoter in emphysema models through DNMT1.
Sections du résumé
BACKGROUND
BACKGROUND
Emphysema is a crucial pathological characteristic of chronic obstructive pulmonary disease (COPD). Oxidative stress, apoptosis and epigenetic mechanisms contribute to the pathogenesis of emphysema. However, an attempt to accurately identify whether these mechanisms interact with each other and how they are triggered has never been conducted.
METHOD
METHODS
The total reactive oxygen species (ROS) level, pulmonary apoptosis and B-cell lymphoma/leukemia-2 (Bcl-2) expression, an apoptosis regulator, were detected in samples from COPD patients. Bisulfite sequencing PCR (BSP) was conducted to observe the alterations in the methylation of the Bcl-2 promoter in specimens. The dysregulation of DNA methyltransferase enzyme 1 (DNMT1), a vital DNA methyltransferase enzyme, in the lungs of patients was confirmed through western blotting. To find out interactions between oxidative stress and DNA methylation in emphysema, mouse models were built with antioxidant treatment and DNMT1 silencing, and were examined with the pulmonary apoptosis, Bcl-2 and DNMT1 levels, and epigenetic alterations of Bcl-2.
RESULTS
RESULTS
Higher ROS levels and pulmonary apoptosis were observed in COPD patients than in healthy controls. Downregulated Bcl-2 expression with increased promoter methylation and DNMT1 protein expression was found in COPD patients. Antioxidant treatment reduced the level of ROS, DNMT1 protein and emphysematous progression in the smoking models. Following DNMT1 blockade, smoking models showed improved lung function, pulmonary apoptosis, emphysematous progression, and increased Bcl-2 protein level with less promoter methylation than emphysema mice.
CONCLUSION
CONCLUSIONS
Cigarette-induced oxidative stress mediates pulmonary apoptosis and hypermethylation of the Bcl-2 promoter in emphysema models through DNMT1.
Identifiants
pubmed: 32883320
doi: 10.1186/s12931-020-01495-w
pii: 10.1186/s12931-020-01495-w
pmc: PMC7469342
doi:
Substances chimiques
Proto-Oncogene Proteins c-bcl-2
0
DNA (Cytosine-5-)-Methyltransferase 1
EC 2.1.1.37
DNMT1 protein, human
EC 2.1.1.37
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
229Subventions
Organisme : National Natural Science Foundation of China
ID : 81370143
Organisme : National Natural Science Foundation of China
ID : 81170036
Organisme : National Natural Science Foundation of China
ID : 81400032
Organisme : Natural Science Foundation of Hunan Province
ID : 09JJ3036
Organisme : Natural Science Foundation of Hunan Province
ID : 2019JJ50877
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