Hepatic response to oxidative injury in long-lived Ames dwarf mice.
Multiple stress resistance pathways were evaluated in the liver of Ames dwarf mice before and after exposure to the oxidative toxin diquat, seeking clues to the exceptional longevity conferred by this mutation. Before diquat treatment, Ames dwarf mice, compared with nonmutant littermate controls, had 2- to 6-fold higher levels of expression of mRNAs for immediate early genes and 2- to 5-fold higher levels of mRNAs for genes dependent on the transcription factor Nrf2. Diquat led to a 2-fold increase in phosphorylation of the stress kinase ERK in control (but not Ames dwarf) mice and to a 50% increase in phosphorylation of the kinase JNK2 in Ames dwarf (but not control) mice. Diquat induction of Nrf2 protein was higher in dwarf mice than in controls. Of 6 Nrf2-responsive genes evaluated, 4 (HMOX, NQO-1, MT-1, and MT-2) remained 2- to 10-fold lower in control than in dwarf liver after diquat, and the other 2 (GCLM and TXNRD) reached levels already seen in dwarf liver at baseline. Thus, livers of Ames dwarf mice differ systematically from controls in multiple stress resistance pathways before and after exposure to diquat, suggesting mechanisms for stress resistance and extended longevity in Ames dwarf mice.
Sun
Liou Y
LY
Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109-0940, USA.
Bokov
Alex F
AF
Richardson
Arlan
A
Miller
Richard A
RA
D000818:Animals; D015153:Blotting, Western; D004178:Diquat / Q000633:toxicity*; D004393:Dwarfism, Pituitary / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000235:genetics; D005721:Glutamate-Cysteine Ligase / Q000235:genetics; D051547:Heme Oxygenase-1 / Q000235:genetics; D006540:Herbicides / Q000633:toxicity; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008136:Longevity / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008668:Metallothionein / Q000235:genetics; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation / Q000187:drug effects; D021122:Protein Subunits / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054481:Thioredoxin Reductase 1 / Q000235:genetics
D006540:Herbicides; D008565:Membrane Proteins; C491054:Mt2 protein, mouse; D051267:NF-E2-Related Factor 2; D021122:Protein Subunits; C525355:metallothionein-1, mouse; D008668:Metallothionein; D004178:Diquat; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D054481:Thioredoxin Reductase 1; C516125:Txnrd1 protein, mouse; D020928:Mitogen-Activated Protein Kinases; D005721:Glutamate-Cysteine Ligase
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