Nitric Oxide Signaling Plays Critical Role in Antioxidant Adaptive Response

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Researchers from Japan have revealed the vital role of nitric oxide signaling in the antioxidant adaptive response. The study, published in the Journal of Biological Chemistry, demonstrates that nitric oxide (NO) triggers the formation of 8-nitroguanosine 3',5'-cyclic monophosphate (8-nitro-cGMP), a nitrated guanine nucleotide that causes protein S-guanylation. This process leads to the activation of Nrf2, a transcription factor that induces antioxidant enzymes, protecting cells from oxidative stress.

Key Takeaways:

  • The study found that NO-dependent formation of 8-nitro-cGMP in C6 glioma cells increased linearly, with a peak value comparable to that of cGMP at 24 hours.
  • The researchers discovered that the amount of 8-nitro-cGMP generated was comparable to or higher than that of cGMP, suggesting that GTP (a substrate of cGMP biosynthesis) may undergo guanine nitration.
  • 8-nitro-cGMP caused S-guanylation of KEAP1 in cells, leading to Nrf2 activation and subsequent induction of antioxidant enzymes, including heme oxygenase-1.
  • Proteomic analysis revealed that 8-nitro-cGMP S-guanylated the Cys(434) of KEAP1, enabling the cell's antioxidant response.
  • The study concludes that the present report is the first substantial corroboration of the biological significance of cellular 8-nitro-cGMP formation and potential roles of 8-nitro-cGMP in the Nrf2-dependent antioxidant response.

Statistics:

  • The study found that 40 microm of 8-nitro-cGMP was present in C6 cells that had been stimulated to express inducible NO synthase with excessive NO production.
  • 8-nitro-cGMP levels increased linearly up to a peak value comparable to that of cGMP at 24 hours, before declining.
  • The amount of 8-nitro-cGMP generated was comparable to or higher than that of cGMP, with cGMP production slightly preceding 8-nitro-cGMP formation in the activated inducible NO synthase-expressing cells.

Sources:

  • Fujii, S., et al. (2010). The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response. Journal of Biological Chemistry, 285(31), 23970-84.
  • Reactive Nitrogen Species (via Kumamoto University, Department of Microbiology)
  • Clinical Oncology Week (via NewsRx.com)