Peroxynitrite activates NF-E2-related factor 2/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: The role of nitric oxide synthase in rat glutathione S-transferase A2 induction

doi:10.1016/S1089-8603(02)00117-9

Nitric Oxide

Volume 7, Issue 4, December 2002, Pages 244-253

https://doi.org/10.1016/S1089-8603(02)00117-9 Get rights and content

Abstract

The protective adaptive response to electrophiles and reactive oxygen species is mediated by the induction of phase II detoxifying genes through antioxidant response elements (AREs). Our previous study showed that sulfur amino acid deprivation (SAAD) produces peroxides and induces rat glutathione S-transferase A2 (rGSTA2) through NF-E2-related factor 2 (Nrf2)/ARE activation via the pathway of phosphatidylinositol 3-kinase (PI3-kinase). The current study was designed to investigate the role of peroxynitrite in Nrf2/ARE activation and rGSTA2 induction. l-Arginine deficiency or N^G-nitro-l-arginine methyl ester (l-NAME) reduced peroxide production induced by SAAD in H4IIE cells. Northern and Western blot analyses revealed that the levels of rGSTA2 mRNA and protein were significantly increased 24 h after incubation of the cells in SAAD medium, which was inhibited by l-arginine deficiency or l-NAME. Subcellular fractionation and gel shift analyses revealed that SAAD increased the level of nuclear Nrf2 and activated ARE, which were also blocked by l-arginine deficiency or l-NAME. Whereas the exogenous NO donor S-nitroso-N-acetyl-penicillamine (SNAP) alone failed to significantly induce rGSTA2, SNAP enhanced SAAD-inducible rGSTA2 expression, verifying the notion that peroxynitrite derived from NO contributes to rGSTA2 induction. 3-Morpholinosydnonimine (SIN-1), which decomposes and yields peroxynitrite, increased the rGSTA2 mRNA and protein levels in a dose-dependent manner. SIN-1 increased the level of nuclear Nrf2 and activated Nrf2/ARE, which was supershifted by anti-Nrf2 and anti-Maf antibodies. SIN-1 increased the activity of PI3-kinase, as monitored by phosphorylation of Akt. SIN-1-inducible rGSTA2 expression was inhibited by PI3-kinase inhibitors. These results provide evidence that peroxynitrite plays an essential role in nuclear translocation of Nrf2 and ARE activation through the pathway of PI3-kinase and that nitric oxide synthase is involved in the induction of rGSTA2.

Section snippets

Materials

$[α-^{32} P]$ dCTP (3000 mCi/mmol) and $[γ-^{32} P]$ ATP (6000 mCi/mmol) were purchased from New England Nuclear (Arlington Heights, IL). Anti-rGSTA1/2 antibody was supplied from Biotrin International (Dublin, Ireland). Alkaline phosphatase-conjugated goat anti-rabbit IgG, minimum essential medium-select amine kit, recombinant protein G–agarose, and 5-bromo-4-chloro-3-indoylphosphate/nitroblue tetrazolium were obtained from Life Technologies (Gaithersburg, MD). Anti-Nrf1, anti-Nrf2, and anti-v-Maf antibodies

NO-dependent rGSTA2 induction by SAAD

Involvement of NO in peroxide production by SAAD. Previous study has shown that peroxide formation is increased by SAAD [10]. In cells loaded with DCFH, oxidation of the dye represents generalized oxidative stress including the oxygen species RO₂, RO, OH (hydroxyl radical), HOCl (hypochlorous acid), and ONOO⁻ (peroxynitrite) [21]. In view of the fact that DCFH is oxidized by peroxynitrite, we first determined whether NOS was involved in the prooxidant production by SAAD. The intensity of DCF

Discussion

Depletion of hepatic GSH increases the susceptibility of animals to free radical-induced tissue damage because GSH plays a critical role in the detoxification of oxidative metabolites produced from endogenous and exogenous molecules. Deprivation of sulfur amino acids from culture medium led to a decrease in the cellular GSH level. Because cysteine is a direct precursor of GSH, the lack of sulfur amino acids causes a time-dependent decrease in the reduced GSH [10], [25]. DCFH oxidation is an

Acknowledgements

This work was financially supported by The Basic Sciences Research Program from Korea Research Foundation (FS0014), Ministry of Education, Republic of Korea.

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Peroxynitrite activates NF-E2-related factor 2/antioxidant response element through the pathway of phosphatidylinositol 3-kinase: The role of nitric oxide synthase in rat glutathione S-transferase A2 induction

Abstract

Section snippets

Materials

NO-dependent rGSTA2 induction by SAAD

Discussion

Acknowledgements

J. Biol. Chem.

Biochem. Biophys. Res. Commun.

Biochim. Biophys. Acta

Biochem. Pharmacol.

Pharmacol. Res.

Toxicol. Lett.

Arch. Biochem. Biophys.

Biochem. Pharmacol.

The glutathione S-transferase supergene family: Regulation of GST and the contribution of the isoenzymes to cancer chemoprotection and drug resistance

Crit. Rev. Biochem. Mol. Biol.

Glutathione-S-transferase as a selective inhibitor of oncogenic ras-p21-induced mitogenic signaling through blockade of activation of Jun by Jun-N-terminal kinase

Ann. Clin. Lab. Sci.