DDAH1 plays dual roles in PM2.5 induced cell death in A549 cells.

2016 
Abstract Background Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an enzyme that can degrade asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase (NOS) inhibitor. Emerging evidence suggests that alterations in the ADMA–DDAH1 pathway are involved in environmental pollution induced airway inflammation. However, the role of DDAH1 in protection against cytotoxicity of ambient airborne particulate matter is unclear. Methods We examined the influence of DDAH1 expression on oxidative stress and cell apoptosis in human type II alveolar epithelial A549 cells exposed to PM 2.5 (particulate matter with an aerodynamic diameter less than 2.5 μM). Results We found that PM 2.5 exposure for 48 h significantly decreased DDAH1 expression. However, knockdown of DDAH1 prior to PM 2.5 exposure actually attenuated the cytotoxicity of PM 2.5 . Cytoprotection in DDAH1 deficient cells was due to increased reactive oxygen species, activation of PI3K–AKT and mitogen-activated protein kinase (MAPK) pathways, subsequent activation of nuclear factor erythroid-2-related factor 2 (Nrf2) and this caused a subsequent reduction in PM 2.5 induced oxidative stress relative to control. DDAH1 depletion also repressed the induction of inducible NOS (iNOS) in PM 2.5 -exposed cells and knockdown of iNOS protected cells against PM 2.5 induced cell death. Interestingly, overexpression of DDAH1 also exerted a protective effect against the cytotoxicity of PM 2.5 and this was associated with a reduction in oxidative stress and upregulation of the anti-apoptotic protein Bcl-2. Conclusions Our data indicate that DDAH1 plays dual roles in protection against cytotoxicity of PM 2.5 exposure, apparently by limiting PM 2.5 induced oxidative stress. General significance Our findings reveal new insights into the role(s) of the DDAH1/ADMA in pulmonary protection against airborne pollutants. This article is part of a Special Issue entitled Air Pollution, edited by Wenjun Ding, Andrew J. Ghio and Weidong Wu.
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