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Influence of SkQ1 on expression of Nrf2 gene, ARE-controlled genes of antioxidant enzymes and their activity in rat blood leukocytes under oxidative stress

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Abstract

The study demonstrated that oxidative stress induced by hyperoxia (0.5 MPa for 90 min) resulted in reduction of mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes (SOD1, CAT, GPx4) in peripheral blood leukocytes of rats. The changes in gene expression profiles under hyperoxia were accompanied by disbalance of activity of antioxidant enzymes in the leukocytes, namely activation of superoxide dismutase and inhibition of catalase, glutathione peroxidase, and glutathione-S-transferase. Pretreatment of rats with SkQ1 (50 nmol/kg for five days) significantly increased mRNA levels of transcription factor Nrf2 and Nrf2-induced genes encoding antioxidant enzymes SOD2 and GPx4 and normalized the transcriptional activity of the SOD1 and CAT genes in the leukocytes in hyperoxia-induced oxidative stress. At the same time, the activity of catalase and glutathione peroxidase was increased, and the activity of superoxide dismutase and glutathione-S-transferase returned to the control level. It is hypothesized that protective effect of SkQ1 in hyperoxia-induced oxidative stress can be realized via a direct antioxidant property and the stimulation of the Keap1/Nrf2 redox-sensitive signaling system.

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Abbreviations

ARE:

antioxidant response element

HBO:

hyperbaric oxygen (therapy)

ROS:

reactive oxygen species

References

  1. Valko, M., Leibfritz, D., Moncol, J., Cronin, M. T., Mazur, M., and Telser, J. (2007. Free radicals and antioxidants in normal physiological functions and human disease, Int. J. Biochem. Cell Biol., 39, 44–84.

    Article  CAS  PubMed  Google Scholar 

  2. Sies, H. (2015. Oxidative stress: a concept in redox biology and medicine, Redox Biol., 4, 180–183.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  3. Zhivotovsky, B., and Orrenius, S. (2010. Cell death mechanisms: cross-talk and role in disease, Exper. Cell Res., 316, 1374–1383.

    Article  CAS  Google Scholar 

  4. Ay, H., Topal, T., Ozler, M., Uysal, B., Korkmaz, A., Oter, S., Ogur, R., and Dundar, K. (2007. Persistence of hyperbaric oxygen-induced oxidative effects after exposure in rat brain cortex tissue, Life Sci., 80, 2025–2029.

    Article  CAS  PubMed  Google Scholar 

  5. Berkelhamer, S. K., Kim, G. A., Radder, J. E., Wedgwood, S., Czech, L., Steinhorn, R. H., and Schumacker, P. T. (2013. Developmental differences in hyperoxia-induced oxidative stress and cellular responses in the murine lung, Free Radic. Biol. Med., 61, 51–60.

    Article  CAS  PubMed  Google Scholar 

  6. Mathieu, D. (2009) Handbook of Hyperbaric Medicine [Russian translation], BINOM, Laboratoriya Znanii, Moscow.

    Google Scholar 

  7. Das, K. C. (2013. Hyperoxia decreases glycolytic capacity, glycolytic reserve and oxidative phosphorylation in MLE12 cells and inhibits complex I and II function, but not complex IV in isolated mouse lung mitochondria, PLoS One, 8, e73358.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Resseguie, E. A., Staversky, R. J., Brookes, P. S., and O’Reilly, M. A. (2015. Hyperoxia activates ATM independent from mitochondrial ROS and dysfunction, Redox Biol., 5, 176–185.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  9. Skulachev, V. P. (2007. A biochemical approach to the problem of aging: “megaproject” on membrane-penetrating ions. The first results and prospects, Biochemistry (Moscow), 72, 1385–1396.

    Article  CAS  Google Scholar 

  10. Plotnikov, E. Y., Silachev, D. N., Chupyrkina, A. A., Danshina, M. I., Jankauskas, S. S., Morosanova, M. A., Stelmashook, E. V., Vasileva, A. K., Goryacheva, E. S., Pirogov, Y. A., Isaev, N. K., and Zorov, D. B. (2010. Newgeneration Skulachev ions exhibiting nephroprotective and neuroprotective properties, Biochemistry (Moscow), 75, 145–150.

    Article  CAS  Google Scholar 

  11. Niture, S. K., Khatri, R., and Jaiswal, A. K. (2014. Regulation of Nrf2–an update, Free Radic. Biol. Med., 66, 34–36.

    Article  Google Scholar 

  12. Forman, H. J., Davies, K. J. A., and Ursini, F. (2014. How do nutritional antioxidants really work: nucleophilic tone and para-hormesis free radical scavenging in vivo, Free Radic. Biol. Med., 66, 24–35.

    Article  CAS  PubMed  Google Scholar 

  13. Vnukov, V. V., Gutsenko, O. I., Milutina, N. P., Ananyan, A. A., Danilenko, A. O., Panina, S. B., and Kornienko, I. V. (2015. Influence of SkQ1 on expression of Nrf2 transcription factor gene, ARE-controlled genes of antioxidant enzymes, and their activity in rat blood leukocytes, Biochemistry (Moscow), 80, 586–591.

    Article  CAS  Google Scholar 

  14. Lukash, A. I., Vnukov, V. V., Ananyan, A. A., Milutina, N. P., and Kvasha, P. N. (1996) Metal-Containing Substances of Blood Plasma in Hyperbaric Oxygenation (Experimental and Clinical Aspects) [in Russian], RSU Publishers, Rostov-onDon.

    Google Scholar 

  15. Boyum, A. (1968. Separation of leukocytes from blood and bone marrow, Scand. J. Clin. Lab. Invest. Suppl., 97, 77–89.

    CAS  PubMed  Google Scholar 

  16. Sirota, N. V. (1999. New approach in studies of adrenalin autoxidation and its use in measurements of superoxide dismutase activity, Vopr. Med. Khim., 3, 14–15.

    Google Scholar 

  17. Korolyuk, M. A., Ivanova, L. I., Maiorova, I. G., and Tokarev, V. E. (1988. Method for measurements of catalase activity, Lab. Delo, 1, 16–19.

    Google Scholar 

  18. Moin, V. M. (1986. Simple and specific approach for determination of glutathione peroxidase activity in erythrocytes, Lab. Delo, 12, 724–727.

    PubMed  Google Scholar 

  19. Habig, W. H., Pabst, M. J., and Jacoby, W. B. (1974. Glutathione-S-transferase: the first step in mercapturic acid formation, J. Biol. Chem. 249, 7130–7139.

    CAS  PubMed  Google Scholar 

  20. Saidov, M. Z., and Pinegin, B. V. (1991. Spectrophotometric method of myeloperoxidase assay in phagocytic cells, Lab. Delo, 3, 56–59.

    PubMed  Google Scholar 

  21. Dluzhevskaya, T. S., Pogorelova, T. N., and Afonin, A. A. (1989. NADPH-oxidase activity in determination of newborn health status, Pediatriya, 3, 44–47.

    Google Scholar 

  22. Cho, H.-Y., Jedlicka, A. E., Reddy, S. P., Kensler, T. W., Yamamoto, M., Zhang, L. Y., and Kleeberger, S. R. (2002. Role of NRF2 in protection against hyperoxic lung injury in mice, Am. J. Respir. Cell Mol. Biol., 26, 175–182.

    Article  CAS  PubMed  Google Scholar 

  23. Cho, H.-Y., Reddy, S. P., De Biase, A., Yamamoto, M., and Kleeberger, S. R. (2005. Gene expression profiling of NRF2-mediated protection against oxidative injury, Free Radic. Biol. Med., 38, 325–343.

    Article  CAS  PubMed  Google Scholar 

  24. Pendyala, S., and Natarajan, V. (2010. Redox regulation of Nox proteins, Respir. Physiol. Neurobiol., 174, 265–271.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Pendyala, S., Gorshkova, I. A., Usatyuk, P. V., He, D., Pennathur, A., Lambeth, J. D., Thannickal, V. J., and Natarajan, V. (2009. Role of Nox4 and Nox2 in hyperoxiainduced reactive oxygen species generation and migration of human lung endothelial cells, Antioxid. Redox. Signal., 11, 747–764.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Kaspar, J. W., Niture, S. K., and Jaiswal, A. K. (2009. Nrf2: INrf2 (Keap1) signaling in oxidative stress, Free Radic. Biol. Med., 47, 1304–1309.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Ma, Q. (2013. Role of Nrf2 in oxidative stress and toxicity, Annu. Rev. Pharmacol. Toxicol., 53, 401–426.

    Article  CAS  PubMed  Google Scholar 

  28. Hayes, J. D., and Dinkova-Kostova, A. T. (2014. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism, Trends Biochem. Sci., 39, 199–216.

    Article  CAS  PubMed  Google Scholar 

  29. Taguchi, K., Motohashi, H., and Yamamoto, M. (2011. Molecular mechanisms of the Keap1–Nrf2 pathway in stress response and cancer evolution, Genes Cells, 16, 123–140.

    Article  CAS  PubMed  Google Scholar 

  30. Lo, S.-C., and Hannink, M. (2008. PGAM5 tethers a ternary complex containing Keap1 and Nrf2 to mitochondria, Exp. Cell Res., 14, 1789–1803.

    Article  Google Scholar 

  31. Dinkova-Kostova, A. T., and Abramov, A. Y. (2015) The emerging role of Nrf2 in mitochondrial function, Free Radic. Biol. Med., doi: 10.1016/j.freeradbiomed.2015.04.036.

    Google Scholar 

  32. Ma, Q. (2010. Transcriptional responses to oxidative stress: pathological and toxicological implications, Pharmacol. Ther., 125, 376–393.

    Article  CAS  PubMed  Google Scholar 

  33. McGrath-Morrow, S., Lauer, T., Yee, M., Neptune, E., Podowski, M., Thimmulappa, R. K., O’Reilly, M., and Biswal, S. (2009. Nrf2 increases survival and attenuates alveolar growth inhibition in neonatal mice exposed to hyperoxia, Am. J. Physiol. Lung Cell. Mol. Physiol., 296, 565–573.

    Article  Google Scholar 

  34. Kwak, M.-K., Itoh, K., Yamamoto, M., and Kensler, T. W. (2002. Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter, Mol. Cell Biol., 22, 2883–2892.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Bryan, H. K., Olayanju, A., Goldring, C. E., and Park, B. K. (2013. The Nrf2 cell defense pathway: Keap1-dependent and -independent mechanisms of regulation, Biochem. Pharmacol., 85, 705–717.

    Article  CAS  PubMed  Google Scholar 

  36. He, X., and Ma, Q. (2009. NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECHassociated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation, Mol. Pharmacol., 76, 1265–1278.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Vnukov, V. V., Milutina, N. P., Ananyan, A. A., Danilenko, A. O., Gutsenko, O. I., and Verbitsky, E. V. (2013. The influence of plastoquinone cation derivative–10(6'-plastoquinonyl)decyltriphenylphosphonium (SkQ1)–on the apoptosis intensity and structural state of rat lymphocyte membranes under oxidative stress induced by the hyperbaric oxygenation, Vestnik SSC RAN, 9, 78–86.

    Google Scholar 

  38. Takaya, K., Suzuki, T., Motohashi, H., Onodera, K., Satomi, S., Kensler, T. W., and Yamamoto, M. (2012. Validation of the multiple sensor mechanism of the Keap1–Nrf2 system, Free Radic. Biol. Med., 53, 817–827.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Biochemistry and Microbiology, Southern Federal University, Academy of Biology and Biotechnology, 344090, Rostov-on-Don, Russia

    V. V. Vnukov, O. I. Gutsenko, N. P. Milutina, I. V. Kornienko, A. A. Ananyan, A. O. Danilenko, S. B. Panina, A. A. Plotnikov & M. S. Makarenko

Authors
  1. V. V. Vnukov
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  2. O. I. Gutsenko
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  3. N. P. Milutina
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  4. I. V. Kornienko
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  5. A. A. Ananyan
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  6. A. O. Danilenko
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  7. S. B. Panina
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  8. A. A. Plotnikov
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  9. M. S. Makarenko
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Correspondence to N. P. Milutina.

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Published in Russian in Biokhimiya, 2015, Vol. 80, No. 12, pp. 1861-1870.

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Vnukov, V.V., Gutsenko, O.I., Milutina, N.P. et al. Influence of SkQ1 on expression of Nrf2 gene, ARE-controlled genes of antioxidant enzymes and their activity in rat blood leukocytes under oxidative stress. Biochemistry Moscow 80, 1598–1605 (2015). https://doi.org/10.1134/S0006297915120081

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  • DOI: https://doi.org/10.1134/S0006297915120081

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