title: Protective effect of rat aldo-keto reductase (AKR1C15) on endothelial cell damage elicited by 4-hydroxy-2-nonenal.
abstract: 4-Hydroxy-2-nonenal (HNE), a major reactive product of lipid peroxidation, is believed to play a central role in atherogenic actions triggered by oxidized lipoproteins. An aldo-keto reductase (AKR) 1C15 efficiently reduces HNE and is distributed in many rat tissues including endothelial cells. In this study, we investigated whether AKR1C15 acts as a protective factor against endothelial damage elicited by HNE and oxidized lipoproteins. Treatment of rat endothelial cells with HNE provoked apoptosis through reactive oxygen species (ROS) formation, mitochondrial dysfunction and caspase activation in the cells. AKR1C15 converted HNE into less toxic 1,4-dihydroxy-2-nonene, and its overexpression markedly decreased the susceptibility of the cells to HNE. The forced expression of AKR1C15 also significantly suppressed the loss of cell viability caused by oxidized low-density lipoprotein and its lipidic fraction. Furthermore, the treatment of the cells with sublethal concentrations of HNE resulted in up-regulation of AKR1C15, which was partially abrogated by the ROS inhibitors. Collectively, these data indicate an anti-atherogenic function of AKR1C15 through the protection of endothelial cells from damage elicited by toxic lipids such as HNE.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu, Japan. matsunagat@gifu-pu.ac.jp
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsunaga
authors.forename: Yuhki
authors.initials: Y
authors.lastname: Shinoda
authors.forename: Yukari
authors.initials: Y
authors.lastname: Inoue
authors.forename: Satoshi
authors.initials: S
authors.lastname: Endo
authors.forename: Ossama
authors.initials: O
authors.lastname: El-Kabbani
authors.forename: Akira
authors.initials: A
authors.lastname: Hara
mesh_terms: D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008074:Lipoproteins / Q000378:metabolism; D008297:Male; D050837:Oxidoreductases Acting on Aldehyde or Oxo Group Donors / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000447:Aldehydes; D008074:Lipoproteins; C560506:AKR1C15 protein, rat; D050837:Oxidoreductases Acting on Aldehyde or Oxo Group Donors; C027576:4-hydroxy-2-nonenal