The ER stress-mediated decrease in DDAH1 expression is involved in formaldehyde-induced apoptosis in lung epithelial cells

• Published in: Food and chemical toxicology 2013-12, Vol.62, p.763-769
• Main Authors: Lim, Seul Ki, Choi, Hyeon, Park, Min Jung, Kim, Dong Il, Kim, Jong Choon, Kim, Gye Yeop, Jeong, Soo Yeong, Rodionov, Roman N., Han, Ho Jae, Yoon, Kyung Chul, Park, Soo Hyun
• Format: Article
• Language: English
• Subjects: Amidohydrolases - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; caspase-3; Cell Line - drug effects; cell viability; DDAH1; DDAH2; endoplasmic reticulum; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Endoplasmic Reticulum Stress - drug effects; epithelial cells; Epithelial Cells - drug effects; Epithelial Cells - metabolism; Epithelial Cells - pathology; ER-stress; Formaldehyde; Formaldehyde - toxicity; Humans; Lung - cytology; Lung - drug effects; Lung epithelial cells; Medical sciences; messenger RNA; nitric oxide; phosphorylation; protein synthesis; proteins; respiratory system; respiratory tract diseases; toxicity; Toxicology
• ISSN: 0278-6915; 1873-6351
• DOI: 10.1016/j.fct.2013.10.014

•Lung epithelial cells were tested for the effect of formaldehyde (FA) on cell death.•FA reduced the mRNA and protein expression level of DDAH1 in A549 cells.•FA induced apoptosis via ER stress activation through a decrease of DDAH1 in lung epithelial cells.•DDAH1 overexpression protected FA-induced ER stress and cell death suggesting its role in FA-induced apoptosis. 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.