Department of Pathology and Geriatrics Center, University of Michigan, Ann Arbor, MI 48109-0940, USA.
FASEB J. 2011 Jan;25(1):398-408. doi: 10.1096/fj.10-164376. Epub 2010 Sep 8.
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.
在暴露于氧化应激毒素百草枯之前和之后，评估了阿姆斯矮小鼠肝脏中的多种应激抵抗途径，以寻找该突变赋予其异常长寿的线索。在百草枯处理之前，与非突变同窝对照相比，阿姆斯矮小鼠的即时早期基因的 mRNA 表达水平高出 2 至 6 倍，并且转录因子 Nrf2 依赖性基因的 mRNA 水平高出 2 至 5 倍。百草枯导致对照（而非阿姆斯矮）小鼠中应激激酶 ERK 的磷酸化增加了 2 倍，而阿姆斯矮小鼠（而非对照）中激酶 JNK2 的磷酸化增加了 50％。与对照组相比，Nrf2 蛋白在矮小鼠中的诱导更高。在评估的 6 个 Nrf2 反应基因中，有 4 个（HMOX、NQO-1、MT-1 和 MT-2）在百草枯处理后仍比对照组低 2 至 10 倍，而另外 2 个（GCLM 和 TXNRD）则达到了基线时已经在矮小鼠肝脏中看到的水平。因此，阿姆斯矮小鼠的肝脏在暴露于百草枯之前和之后在多种应激抵抗途径中与对照组存在系统差异，这表明阿姆斯矮小鼠具有应激抵抗和延长寿命的机制。
