title: The ER stress-mediated decrease in DDAH1 expression is involved in formaldehyde-induced apoptosis in lung epithelial cells.
abstract: Formaldehyde (FA) is toxic to the respiratory system, and nitric oxide (NO) dysfunction stimulates the onset of respiratory diseases. The involvement of dimethylarginine dimethylaminohydrolase (DDAH), the l-arginine analogue asymmetric dimethylarginine (ADMA) degrading enzyme, in FA-induced cell death in lung epithelial cells has not been investigated. In this study, we assessed the effect of FA on DDAH expression and endoplasmic reticulum (ER) stress in A549 cells. We also investigated the preventive effect of DDAH overexpression on ER stress and apoptosis in FA-induced cell death. FA decreased viability in A549 cells and decreased DDAH1 and DDAH2 mRNA and protein expression in a time-dependent manner (>4h). This coincided with increased phosphorylation of the ER stress proteins IRE1α, PERK, and eIF-2α, as well as increased expression of pro-apoptotic proteins such as Bax, C/EPB homologous protein (CHOP), cleaved PARP, and cleaved caspase-3, but decreased expression of the anti-apoptotic protein Bcl-2. ADMA treatment mimicked the effect of FA. Overexpression of DDAH1, but not DDAH2, prevented FA-induced decreases in cell viability, phosphorylation of IRE1α, PERK, and eIF2α, and expression of CHOP. Effects of DDAH1 overexpression, but not DDAH2 overexpression, restored FA-induced increases in Bax, CHOP, cleaved PARP, cleaved caspase-3 and decreases in Bcl-2. In conclusion, FA induces apoptosis of lung epithelial cells via a decrease of DDAH1 through ER stress.
authors.affiliation: Bio-therapy Human Resources Center, College of Veterinary Medicine, Chonnam National University, Gwangju 500-757, South Korea.
authors.forename: Seul Ki
authors.initials: SK
authors.lastname: Lim
authors.forename: Hyeon
authors.initials: H
authors.lastname: Choi
authors.forename: Min Jung
authors.initials: MJ
authors.lastname: Park
authors.forename: Dong Il
authors.initials: DI
authors.lastname: Kim
authors.forename: Jong Choon
authors.initials: JC
authors.lastname: Kim
authors.forename: Gye Yeop
authors.initials: GY
authors.lastname: Kim
authors.forename: Soo Yeong
authors.initials: SY
authors.lastname: Jeong
authors.forename: Roman N
authors.initials: RN
authors.lastname: Rodionov
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
authors.forename: Kyung Chul
authors.initials: KC
authors.lastname: Yoon
authors.forename: Soo Hyun
authors.initials: SH
authors.lastname: Park
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002460:Cell Line / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005557:Formaldehyde / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000166:cytology* / Q000187:drug effects
chemical_list: D005557:Formaldehyde; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: Apoptosis; DDAH1; DDAH2; ER-stress; Formaldehyde; Lung epithelial cells