title: Aldo-keto reductase 1C15 as a quinone reductase in rat endothelial cell: its involvement in redox cycling of 9,10-phenanthrenequinone.
abstract: 9,10-Phenanthrenequinone (9,10-PQ), a redox-active quinone in diesel exhausts, triggers cellular apoptosis via reactive oxygen species (ROS) generation in its redox cycling. This study found that induction of CCAAT/enhancer-binding protein-homologous protein (CHOP), a pro-apoptotic factor derived from endoplasmic reticulum stress, participates in the mechanism of rat endothelial cell damage. The 9,10-PQ-mediated CHOP induction was strengthened by a proteasome inhibitor (MG132) and the MG132-induced cell sensitization to the 9,10-PQ toxicity was abolished by a ROS inhibitor, suggesting that ROS generation and consequent proteasomal dysfunction are responsible for the CHOP up-regulation caused by 9,10-PQ. Aldo-keto reductase (AKR) 1C15 expressed in rat endothelial cells reduced 9,10-PQ into 9,10-dihydroxyphenanthrene concomitantly with superoxide anion formation, implying its participation in evoking the 9,10-PQ-redox cycling. The 9,10-PQ-induced damage was augmented by AKR1C15 over-expression. 9,10-PQ also provoked the AKR1C15 up-regulation, which sensitized against the quinone toxicity. These results suggest the presence of a negative feedback loop exacerbating the quinone toxicity in rat endothelial cells.
authors.affiliation: Laboratory of Biochemistry, Gifu Pharmaceutical University, Gifu 501-1196, 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: Yuki
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Mariko
authors.initials: M
authors.lastname: Haga
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: D000429:Alcohol Oxidoreductases / Q000378:metabolism*; D000449:Aldehyde Reductase; D000074408:Aldo-Keto Reductases; D000818:Animals; D023081:CCAAT-Binding Factor / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007976:Leupeptins / Q000494:pharmacology; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010616:Phenanthrenes / Q000378:metabolism*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D023081:CCAAT-Binding Factor; D007976:Leupeptins; D010616:Phenanthrenes; D017382:Reactive Oxygen Species; C005399:9,10-phenanthrenequinone; D000429:Alcohol Oxidoreductases; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase; D016660:NAD(P)H Dehydrogenase (Quinone); C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D020169:Caspases; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde