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.

Shema Oral Liquid Ameliorates the Severity of LPS-Induced COPD via Regulating DNMT1

“…DNMTs-mediated aberrant methylation is linked to the pathogenesis and development of COPD ( Adcock et al, 2011 ). DNMT1 expression in the lung tissue from COPD patients was higher than that in the lung tissue from non-smokers ( Zeng et al, 2020 ).…”

Prohibitin Protects Pulmonary Microvascular Endothelial Cells Against Cigarette Smoke Extract-Induced Cell Apoptosis and Inflammation

“…Morphometry was quantified by the values of mean linear intercept (MLI) at a magnification of 100× as previously described. 18 MLI was assessed by dividing the length of a line drawn across the section by the total number of intercepts encountered in 36 lines per sample, and 10 random fields per sample were observed by microscopy. The numbers of apoptotic cells in longitudinal lung sections from control and emphysema mice were quantified by In-situ Apoptosis Detection Kit (Nanjing Keygen Biotech, China).…”

Senescence: Pathogenic Driver in Chronic Obstructive Pulmonary Disease

“…Venetoclax was the first selective BCL-2 inhibitor to be approved for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia [186]. Zeng, et al suggested the involvement of BCL-2 in the pathogenesis of COPD [187]. BCL-2 inhibitors may have anti-neoplastic as well as anti-inflammatory and anti-aging properties.…”