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Oxidative stress mediates the apoptosis and epigenetic modification of the Bcl-2 promoter via DNMT1 in a cigarette smoke-induced emphysema model.

Abstract：

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: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: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:Cigarette-induced oxidative stress mediates pulmonary apoptosis and hypermethylation of the Bcl-2 promoter in emphysema models through DNMT1.

journal_name

Respir Res

journal_title

Respiratory research

authors

Zeng H,Li T,He X,Cai S,Luo H,Chen P,Chen Y

doi

10.1186/s12931-020-01495-w

subject

Has Abstract

pub_date

2020-09-03 00:00:00

pages

229

issue

eissn

1465-9921

issn

1465-993X

pii

10.1186/s12931-020-01495-w

journal_volume

pub_type

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Oxidative stress mediates the apoptosis and epigenetic modification of the Bcl-2 promoter via DNMT1 in a cigarette smoke-induced emphysema model.