title: Aldose reductase regulates acrolein-induced cytotoxicity in human small airway epithelial cells.
abstract: Aldose reductase (AR), a glucose-metabolizing enzyme, reduces lipid aldehydes and their glutathione conjugates with more than 1000-fold efficiency (Km aldehydes 5-30 µM) relative to glucose. Acrolein, a major endogenous lipid peroxidation product as well as a component of environmental pollutants and cigarette smoke, is known to be involved in various pathologies including atherosclerosis, airway inflammation, COPD, and age-related disorders, but the mechanism of acrolein-induced cytotoxicity is not clearly understood. We have investigated the role of AR in acrolein-induced cytotoxicity in primary human small airway epithelial cells (SAECs). Exposure of SAECs to varying concentrations of acrolein caused cell death in a concentration- and time-dependent manner. AR inhibition by fidarestat prevented the low-dose (5-10 µM) but not the high-dose (>10 µM) acrolein-induced SAEC death. AR inhibition protected SAECs from low-dose (5 µM) acrolein-induced cellular reactive oxygen species (ROS). Inhibition of acrolein-induced apoptosis by fidarestat was confirmed by decreased condensation of nuclear chromatin, DNA fragmentation, comet tail moment, and annexin V fluorescence. Further, fidarestat inhibited acrolein-induced translocation of the proapoptotic proteins Bax and Bad from the cytosol to the mitochondria and that of Bcl2 and BclXL from the mitochondria to the cytosol. Acrolein-induced cytochrome c release from mitochondria was also prevented by AR inhibition. The mitogen-activated protein kinases (MAPKs), such as extracellular signal-regulated kinases 1 and 2, stress-activated protein kinase/c-Jun NH2-terminal kinase, and p38MAPK, and c-Jun were transiently activated in airway epithelial cells by acrolein in a concentration- and time-dependent fashion, which was significantly prevented by AR inhibition. These results suggest that AR inhibitors could prevent acrolein-induced cytotoxicity in the lung epithelial cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: Umesh C S
authors.initials: UCS
authors.lastname: Yadav
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA.
authors.forename: K V
authors.initials: KV
authors.lastname: Ramana
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX 77555, USA. Electronic address: ssrivast@utmb.edu.
authors.forename: Satish K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000171:Acrolein / Q000633:toxicity*; D000449:Aldehyde Reductase / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001980:Bronchi / Q000187:drug effects / Q000201:enzymology; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000009:adverse effects / Q000378:metabolism; D020545:Respiratory Mucosa / Q000187:drug effects* / Q000201:enzymology*; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D048289:Imidazolidines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000171:Acrolein; C077139:fidarestat; D000449:Aldehyde Reductase
keywords: Acrolein; Airway epithelial cells; Aldose reductase; Apoptosis; COPD; Cytotoxicity; Free radicals