title: Molecular mechanisms of ALDH3A1-mediated cellular protection against 4-hydroxy-2-nonenal.
abstract: Evidence suggests that aldehydic molecules generated during lipid peroxidation (LPO) are causally involved in most pathophysiological processes associated with oxidative stress. 4-Hydroxy-2-nonenal (4-HNE), the LPO-derived product, is believed to be responsible for much of the cytotoxicity. To counteract the adverse effects of this aldehyde, many tissues have evolved cellular defense mechanisms, which include the aldehyde dehydrogenases (ALDHs). Our laboratory has previously characterized the tissue distribution and metabolic functions of ALDHs, including ALDH3A1, and demonstrated that these enzymes may play a significant role in protecting cells against 4-HNE. To further characterize the role of ALDH3A1 in the oxidative stress response, a rabbit corneal keratocyte cell line (TRK43) was stably transfected to overexpress human ALDH3A1. These cells were studied after treatment with 4-HNE to determine their abilities to: (a) maintain cell viability, (b) metabolize 4-HNE and its glutathione conjugate, (c) prevent 4-HNE-protein adduct formation, (d) prevent apoptosis, (e) maintain glutathione homeostasis, and (f) preserve proteasome function. The results demonstrated a protective role for ALDH3A1 against 4-HNE. Cell viability assays, morphological evaluations, and Western blot analyses of 4-HNE-adducted proteins revealed that ALDH3A1 expression protected cells from the adverse effects of 4-HNE. Based on the present results, it is apparent that ALDH3A1 provides exceptional protection from the adverse effects of pathophysiological concentrations of 4-HNE such as may occur during periods of oxidative stress.
authors.affiliation: Molecular Toxicology and Environmental Health Sciences Program, Department of Pharmaceutical Sciences, University of Colorado AMC, Aurora, CO 80045, USA.
authors.forename: William
authors.initials: W
authors.lastname: Black
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.forename: Akiko
authors.initials: A
authors.lastname: Matsumoto
authors.forename: David C
authors.initials: DC
authors.lastname: Thompson
authors.forename: Natalie
authors.initials: N
authors.lastname: Lassen
authors.forename: Aglaia
authors.initials: A
authors.lastname: Pappa
authors.forename: Vasilis
authors.initials: V
authors.lastname: Vasiliou
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D003315:Cornea / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011817:Rabbits
chemical_list: D000447:Aldehydes; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; D046988:Proteasome Endopeptidase Complex; C027576:4-hydroxy-2-nonenal