title: Involvement of B-cell CLL/lymphoma 2 promoter methylation in cigarette smoke extract-induced emphysema.
abstract: 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'-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 ± 7.55)% vs (6.28 ± 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 ± 0.08 vs 0.49 ± 0.11, (3.82 ± 1.34)% vs (35.68 ± 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 anti-apoptotic 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.
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Huihui
authors.initials: H
authors.lastname: Zeng
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Respiratory Medicine, The First Hospital of Changsha, Changsha, Hunan 410011, China.
authors.forename: Xianglong
authors.initials: X
authors.lastname: Kong
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Peng
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Luo
authors.affiliation: Department of Respiratory Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China pingchen0731@126.com.
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology; D000077209:Decitabine; D004646:Emphysema / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D012906:Smoke / Q000009:adverse effects*; D012907:Smoking / Q000009:adverse effects
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D012906:Smoke; D000077209:Decitabine; D001374:Azacitidine
keywords: Apoptosis; B-cell CLL/lymphoma 2; emphysema; methylation