Mouse aldo-keto reductase AKR7A5 protects V79 cells against 4-hydroxynonenal-induced apoptosis.
We have developed transgenic Chinese hamster V79 cell lines in order to examine the potential for a mouse aldo-keto reductase, AKR7A5, to protect against the toxicity of 4-hydroxynonenal (4-HNE) and related toxic aldehydes. Stable expression of mouse AKR7A5 in V79 cells conferred four-fold increased resistance to 4-HNE cytotoxicity using the MTT assay compared to empty vector-transfected V79 cells. Cells expressing AKR7A5 showed a decrease in mutation rate compared to control cells in the presence of 4-HNE as measured by HGPRT mutagenicity assay. Furthermore, the cells expressing AKR7A5 showed decreased 4-HNE-induced caspase-3 activity in both a time and dose-dependent manner compared to control cells. These results show that in V79 cells 4-HNE mediates apoptosis via caspase-3 activation and that the AKR7A5 enzyme is able to metabolize 4-HNE in cells, thereby attenuating 4-HNE-induced apoptosis. AKR7A isozymes may therefore be important in protecting against toxic aldehydes derived from lipid peroxidation in vivo.
Li
Dan
D
Department of Bioscience, University of Strathclyde, Glasgow G1 1XW, United Kingdom.
Hinshelwood
Alison
A
Gardner
Rachel
R
McGarvie
Gail
G
Ellis
Elizabeth M
EM
D000429:Alcohol Oxidoreductases / Q000502:physiology*; D000449:Aldehyde Reductase; D000447:Aldehydes / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000074408:Aldo-Keto Reductases; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D015853:Cysteine Proteinase Inhibitors / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015227:Lipid Peroxidation / Q000187:drug effects; D051379:Mice; D009152:Mutagenicity Tests; D013778:Tetrazolium Salts; D013844:Thiazoles; D014162:Transfection
D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; C000614209:AKR7A5 protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; C022616:thiazolyl blue; C027576:4-hydroxy-2-nonenal