P 088 - p38α and NF-κB regulate antioxidant defense in the liver through an age-dependent mechanism

Abstract

p38α MAPK is a sensor of oxidative stress. The aim of this work was to assess the role of p38α in the regulation of the antioxidant defense in the liver with aging. Livers ofyoung and old wild type (WT) and p38α liver-specific knock out (KO) mice were used to determine glutathione redox status by mass spectrometry; malondialdehyde (MDA) levels by HPLC; mRNA expression of glutamate cysteine ligase (Gclc), Sod1, Sod2 and catalase by RT-PCR and nuclear levels of NF-κB subunit p65 by western-blotting. Chromatin immunoprecipitation (ChIP) assay of p65 was performed. Young KO liver exhibited increased in GSSG/GSH ratio and MDA levels when are compared with young WT mice. However, old KO mice had lower hepatic GSSG/GSH ratio and MDA levels than young KO mice. The mRNA expression of Gclc, Sod1, Sod2 and catalase was decreased in young KO mice compared with WT young mice. In contrast, these antioxidant enzymes were up-regulated in KO old mice regard to WT. p65 was markedly phosphorylated in the nucleus of WT young and old KO mice. ChIP assay of p65 confirmed the recruitment of p65 to the promoters of antioxidant genes in WT young and KO old mice. Deficiency of p38α in the liver causes dramatic down-regulation of antioxidant enzymes in young mice, but triggers adaptive up-regulation in the long term via NF-κB to enhance the antioxidant defense in old p38α KO mice.