Protective Effect of Demethylation Treatment on Cigarette Smoke Extract–Induced Mouse Emphysema Model

Zhang, Hongliang; Chen, Ping; Zeng, Huihui; Zhang, Yan; Peng, Hong; Chen, Yan; He, Zhijun

doi:10.1254/jphs.13072fp

Cited by 27 publications

(36 citation statements)

References 22 publications

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“…It is an inhibitor of DNA methyltransferase, which triggers demethylation, leading to changes in gene reactivation [16], sparking interest in its use as a potential therapeutic agent. It has been demonstrated that the demethylation treatment can protect against CSE-induced emphysema in an animal model [14,15]. In our study, the dysfunction of EPCs, decreased expression of eNOS, and increased expression of p16(INK4a) caused by CSE could be partly reversed by Dec.…”

Section: Discussionsupporting

confidence: 59%

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Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction

Chen

Hou

et al. 2017

Med Sci Monit

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BackgroundEndothelial dysfunction is an important pathophysiologic feature in many smoke-related diseases. Endothelial progenitor cells (EPCs) are the precursors of endothelial cells and play a fundamental role in the maintenance of endothelial integrity and function. Endothelial nitric oxide synthase (eNOS) is the dominant NOS isoform in the vasculature and plays a central role in the maintenance of endothelial homeostasis. p16(INK4a) is a cyclin-dependent kinase inhibitor and could be regarded as a major dominant senescence gene. The present study aimed to determine whether the expression of eNOS and p16(INK4a) in EPCs is related to EPCs function and the possible epigenetic mechanism, if any.Material/MethodsWe investigated EPCs capacity for proliferation, adhesion, and secretion, and the expression of eNOS and p16(INK4a) in EPCs which were altered by cigarette smoke extract (CSE) in vitro. Furthermore, Decitabine (Dec), an agent of demethylation, was used to examine whether it could alter the changes induced by CSE.ResultsThe present study demonstrated that EPCs altered by CSE in vitro displayed decreased capacities of proliferation, adhesion, and secretion, which was accompanied by decreased eNOS expression and increased p16(INK4a) expression in EPCs. Furthermore, Dec could alleviate the changes in the expression of eNOS and p16(INK4a), and protect against the EPCs dysfunction caused by CSE.ConclusionsThe decreased eNOS expression and increased p16(INK4a) expression was associated with dysfunction of EPCs caused by CSE. The mechanism of methylation, one of the most common epigenetic mechanism, may be involved in the EPCs dysfunction caused by CSE.

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Section: Discussionsupporting

confidence: 59%

“…It has been demonstrated that a demethylation agent can alleviate emphysema in an animal model [14,15]. Decitabine (Dec) is the most widely used agent of demethylation; it triggers demethylation, leading to a consecutive reactivation of epigenetically silenced genes in vitro and in vivo [16].…”

Section: Introductionmentioning

confidence: 99%

Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction

Chen

Hou

et al. 2017

Med Sci Monit

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“…Our previous research 21,24 and this research found that CSE injection lead emphysematous change and abnormality of pulmonary function. Cigarette smoke was inhaled into the lung and diffused into the mucus and the blood as liquor phase.…”

Section: Discussionmentioning

confidence: 51%

Involvement of B-cell CLL/lymphoma 2 promoter methylation in cigarette smoke extract-induced emphysema

Zeng

Shi

Kong

et al. 2016

Exp Biol Med (Maywood)

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Abnormal apoptotic events play an important role in the pathogenesis of emphysema. The B-cell CLL/lymphoma 2 (Bcl-2) family proteins are essential and critical regulators of apoptosis. We determined whether the anti-apoptotic Bcl-2 play a role in the cigarette smoke extract (CSE)-induced emphysema. Furthermore, given the involvement of epigenetics in chronic obstructive pulmonary disease, we hypothesized that the deregulation of Bcl-2 might be caused by gene methylation. The emphysema in BALB/C mice was established by intraperitoneally injection of CSE. 5-aza-2 0 -deoxycytidine (AZA; a demethylation reagent) and phosphate-buffered saline were also administered intraperitoneally as CSE. TUNEL assay was used to assess apoptotic index of pulmonary cells. The methylation status of CpG dinucleotides within the Bcl-2 promoter was observed in all groups by bisulfite sequencing PCR. Pulmonary expression of Bcl-2, Bax, and cytochrome C were measured after four weeks of treatment. The apoptotic index of pulmonary cells in CSE injection group was much higher than control ((25.88 AE 7.55)% vs. (6.28 AE 2.96)%). Compared to control mice, decreased expression of Bcl-2 and high methylation of Bcl-2 promoter was observed in CSE injected mice (0.88 AE 0.08 vs. 0.49 AE 0.11, (3.82 AE 1.34)% vs. (35.68 AE 5.99)%, P < 0.01).CSE treatment induced lung cell apoptosis and decreased lung function. AZA treatment increased Bcl-2 expression with Bcl-2 promoter demethylation. AZA also alleviated the lung cell apoptosis and function failure caused by CSE treatment. The decreased expression of antiapoptotic Bcl-2 might account for the increased apoptosis in CSE induced-emphysema. Apparently, epigenetic alternation played a role in this deregulation of Bcl-2 expression, and it might support the involvement of epigenetic events in the pathogenesis of emphysema.

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“…Thus, several nongenotoxic chemicals have been found to affect gene function through changes in DNA methylation (27). For example, the nongenotoxic rodent carcinogen phenobarbital induces global hypomethylation and regional hypermethylation in rodent livers (28,3,29).…”

Section: Introductionmentioning

confidence: 99%

BCL2 promotor methylation and miR-15a/16-1 upregulation is associated with sanguinarine-induced apoptotic death in rat HSC-T6 cells

Zhang

Chen

et al. 2015

Journal of Pharmacological Sciences

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Previous studies show that several pathways are involved in sanguinarine-induced apoptotic cell death, including AKT downregulation, inhibition of NF-kB activation, mediation of ROS production, downregulation of anti-apoptosis proteins XIAP and cIAP-1, upregulation of BAX, and downregulation of BCL2. In this study, we found out that the quenching of ROS generation by N-acetyl-l-cysteine (NAC), a scavenger of ROS, reversed sanguinarine-induced apoptosis effects, also we found out that sanguinarine-induced rat hepatic stellate T6 cells (HSC-T6 cells) apoptosis was correlated with the generation of increased ROS, which was followed by the activation of caspase-8 (-3, -6, and -9), and the decreasing in the miltochondrial membrane potential (MMP) and the down-regulation of anti-apoptotic protein Bcl-2. It is not clear whether BCL2's downregulation relates to its promoter methylation and miR-15a/16-1 expression which can bind to BCL2 3'-UTR (un-translation reagon). We showed that sanguinarine-induced down regulation of BCL2 was associated with the increased methylation rate of BCL2 promotor district and the increased expression of miR-15a/16-1. HSC-T6 cells treatment with 5-Aza-2'-deoxycytidine (5'-Aza-CdR) impeded sanguinarine-induced BCL2 promotor district methylation and recovered BCL2's expression. Over expression of BCL2 using pEGFP-N1 vector decreased sanguinarine-induced HSC-T6 cells apoptotic death significantly but not completely. These observations clearly showed that BCL2 down regulation was associated with its promoter methylation and miR-15a/16-1 upregulation in sanguinarine-induced Rat HSC-T6 cells.

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Protective Effect of Demethylation Treatment on Cigarette Smoke Extract–Induced Mouse Emphysema Model

Cited by 27 publications

References 22 publications

Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction

Cigarette Smoke Extract Changes Expression of Endothelial Nitric Oxide Synthase (eNOS) and p16(INK4a) and is Related to Endothelial Progenitor Cell Dysfunction

Involvement of B-cell CLL/lymphoma 2 promoter methylation in cigarette smoke extract-induced emphysema

BCL2 promotor methylation and miR-15a/16-1 upregulation is associated with sanguinarine-induced apoptotic death in rat HSC-T6 cells

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