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Novel mitochondria-targeted antioxidants, “Skulachev-Ion” derivatives, accelerate dermal wound healing in animals

Abstract

It is shown that the novel mitochondria-targeted antioxidant SkQ1, (10-(6′-plastoquinonyl) decyltriphenylphosphonium) stimulates healing of full-thickness dermal wounds in mice and rats. Treatment with nanomolar doses of SkQ1 in various formulations accelerated wound cleaning and suppressed neutrophil infiltration at the early (7 h) steps of inflammatory phase. SkQ1 stimulated formation of granulation tissue and increased the content of myofibroblasts in the beginning of regenerative phase of wound healing. Later this effect caused accumulation of collagen fibers. Local treatment with SkQ1 stimulated re-epithelization of the wound. Lifelong treatment of mice with SkQ1 supplemented with drinking water strongly stimulated skin wounds healing in old (28 months) animals. In an in vitro model of wound in human cell cultures, SkQ1 stimulated movement of epitheliocytes and fibroblasts into the “wound”. Myofibroblast differentiation of subcutaneous fibroblasts was stimulated by SkQ1. It is suggested that SkQ1 stimulates wound healing by suppression of the negative effects of oxidative stress in the wound and also by induction of differentiation. Restoration of regenerative processes in old animals is consistent with the “rejuvenation” effects of SkQ1, which prevents some gerontological diseases.

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Abbreviations

DMEM:

Dulbecco’s modified Eagle’s medium

ICAM1:

intercellular adhesion molecule-1

MitoQ:

10-(6′-ubiquinonyl) decyltriphenylphosphonium

ROS:

reactive oxygen species

SkQ1:

10-(6′-plastoquinonyl) decyltriphenylphosphonium

TGFβ1:

transforming growth factor β1

TNFα:

tumor necrosis factor β

VCAM1:

vascular cell adhesion molecule-1

References

  1. Singer, A. J., and Clark, R. A. (1999) N. Engl. J. Med., 341, 738–746.

    Article  CAS  PubMed  Google Scholar 

  2. Hinz, B. (2007) J. Invest. Dermatol., 127, 526–537.

    Article  CAS  PubMed  Google Scholar 

  3. Hinz, B., Phan, S. H., Thannickal, V. J., Galli, A., Bochaton-Piallat, M. L., and Gabbiani, G. (2007) Am. J. Pathol., 170, 1807–1816.

    Article  CAS  PubMed  Google Scholar 

  4. Roy, S., Khanna, S., Nallu, K., Hunt, T. K., and Sen, C. K. (2006) Mol. Ther., 13, 211–220.

    Article  CAS  PubMed  Google Scholar 

  5. Ojha, N., Roy, S., He, G., Biswas, S., Velayutham, M., Khanna, S., Kuppusamy, P., Zweier, J. L., and Sen, C. K. (2008) Free Radic. Biol. Med., 44, 682–691.

    Article  CAS  PubMed  Google Scholar 

  6. Sen, C. K., and Roy, S. (2008) Biochim. Biophys. Acta, 1780, 1348–1361.

    CAS  PubMed  Google Scholar 

  7. Roy, S., Khanna, S., and Sen, C. K. (2008) Free Radic. Biol. Med., 44, 180–192.

    Article  CAS  PubMed  Google Scholar 

  8. Galeano, M., Torre, V., Deodato, B., Campo, G. M., Colonna, M., Sturiale, A., Squadrito, F., Cavallari, V., Cucinotta, D., Buemi, M., and Altavilla, D. (2001) Surgery, 129, 467–477.

    CAS  PubMed  Google Scholar 

  9. Babior, B. M. (2000) Am. J. Med., 109, 33–44.

    Article  CAS  PubMed  Google Scholar 

  10. Babior, B. M. (2000) IUBMB Life, 50, 267–269.

    Article  CAS  PubMed  Google Scholar 

  11. Chernyak, B. V., Izyumov, D. S., Lyamzaev, K. G., Pashkovskaya, A. A., Pletjushkina, O. Y., Antonenko, Y. N., Sakharov, D. V., Wirtz, K. W., and Skulachev, V. P. (2006) Biochim. Biophys. Acta, 1757, 525–534.

    Article  CAS  PubMed  Google Scholar 

  12. Skulachev, V. P. (2007) Biochemistry (Moscow), 72, 1385–1396.

    CAS  PubMed  Google Scholar 

  13. Antonenko, Y. N., Avetisyan, A. V., Bakeeva, L. E., Chernyak, B. V., Chertkov, V. A., Domnina, L. V., Ivanova, O. Y., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Muntyan, M. S., Nepryakhina, O. K., Pashkovskaya, A. A., Pletjushkina, O. Y., Pustovidko, A. V., Roginsky, V. A., Rokitskaya, T. I., Ruuge, E. K., Saprunova, V. B., Severina, I. I., Simonyan, R. A., Skulachev, I. V., Skulachev, M. V., Sumbatyan, N. V., Sviryaeva, I. V., Tashlitsky, V. N., Vassiliev, J. M., Vyssokikh, M. Y., Yaguzhinsky, L. S., Zamyatnin, A. A., Jr., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1273–1287.

    CAS  PubMed  Google Scholar 

  14. Antonenko, Y. N., Roginsky, V. A., Pashkovskaya, A. A., Rokitskaya, T. I., Kotova, E. A., Zaspa, A. A., Chernyak, B. V., and Skulachev, V. P. (2008) J. Membr. Biol., 222, 141–149.

    Article  CAS  PubMed  Google Scholar 

  15. Skulachev, V. P., Anisimov, V. N., Antonenko, Y. N., Bakeeva, L. E., Chernyak, B. V., Erichev, V. P., Filenko, O. F., Kalinina, N. I., Kapelko, V. I., Kolosova, N. G., Kopnin, B. P., Korshunova, G. A., Lichinitser, M. R., Obukhova, L. A., Pasyukova, E. G., Pisarenko, O. I., Roginsky, V. A., Ruuge, E. K., Senin, I. I., Severina, I. I., Skulachev, M. V., Spivak, I. M., Tashlitsky, V. N., Tkachuk, V. A., Vyssokikh, M. Y., Yaguzhinsky, L. S., and Zorov, D. B. (2009) Biochim. Biophys. Acta, 1787, 437–461.

    Article  CAS  PubMed  Google Scholar 

  16. Agapova, L. S., Chernyak, B. V., Domnina, L. V., Dugina, V. B., Efimenko, A. Y., Fetisova, E. K., Ivanova, O. Y., Kalinina, N. I., Khromova, N. V., Kopnin, B. P., Kopnin, P. B., Korotetskaya, M. V., Lichinitser, M. R., Lukashev, A. L., Pletjushkina, O. Y., Popova, E. N., Skulachev, M. V., Shagieva, G. S., Stepanova, E. V., Titova, E. V., Tkachuk, V. A., Vasiliev, J. M., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1300–1316.

    Article  CAS  Google Scholar 

  17. Bakeeva, L. E., Barskov, I. V., Egorov, M. V., Isaev, N. K., Kapelko, V. I., Kazachenko, A. V., Kirpatovsky, V. I., Kozlovsky, S. V., Lakomkin, V. L., Levina, S. B., Pisarenko, O. I., Plotnikov, E. Y., Saprunova, V. B., Serebryakova, L. I., Skulachev, M. V., Stelmashook, E. V., Studneva, I. M., Tskitishvili, O. V., Vasilyeva, A. K., Victorov, I. V., Zorov, D. B., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1288–1299.

    Article  CAS  Google Scholar 

  18. Neroev, V. V., Archipova, M. M., Bakeeva, L. E., Fursova, A. Z., Grigorian, E. N., Grishanova, A. Y., Iomdina, E. N., Ivashchenko, Z., Katargina, L. A., Khoroshilova-Maslova, I. P., Kilina, O. V., Kolosova, N. G., Kopenkin, E. P., Korshunov, S. S., Kovaleva, N. A., Novikova, Y. P., Philippov, P. P., Pilipenko, D. I., Robustova, O. V., Saprunova, V. B., Senin, I. I., Skulachev, M. V., Sotnikova, L. F., Stefanova, N. A., Tikhomirova, N. K., Tsapenko, I. V., Shchipanova, A. I., Zinovkin, R. A., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1317–1328.

    Article  CAS  Google Scholar 

  19. Anisimov, V. N., Bakeeva, L. E., Egormin, P. A., Filenko, O. F., Isakova, E. F., Manskikh, V. N., Mikhelson, V. M., Panteleeva, A. A., Pasyukova, E. G., Pilipenko, D. I., Piskunova, T. S., Popovich, I. G., Roshchina, N. V., Rybina, O. Y., Saprunova, V. B., Samoylova, T. A., Semenchenko, A. V., Skulachev, M. V., Spivak, I. M., Tsybul’ko, E. A., Tyndyk, M. L., Vyssokikh, M. Y., Yurova, M. N., Zabezhinsky, M. A., and Skulachev, V. P. (2008) Biochemistry (Moscow), 73, 1329–1342.

    CAS  PubMed  Google Scholar 

  20. Yudanova, T. N., Skokova, I. F., Aleshina, E. Y., and Gal’braikh, L. S. (2001) Fiber Chem., 33, 20–24.

    Article  CAS  Google Scholar 

  21. Montesano, R., Saint Vincent, L., Drevon, C., and Tomatis, L. (1975) Int. J. Cancer, 16, 550–558.

    Article  CAS  PubMed  Google Scholar 

  22. Fraticelli, A., Serrano, C. V., Jr., Bochner, B. S., Capogrossi, M. C., and Zweier, J. L. (1996) Biochim. Biophys. Acta, 1310, 251–259.

    Article  PubMed  Google Scholar 

  23. Klyubin, I. V., Kirpichnikova, K. M., and Gamaley, I. A. (1996) Eur. J. Cell Biol., 70, 347–351.

    CAS  PubMed  Google Scholar 

  24. Curzio, M., Esterbauer, H., and Dianzani, M. U. (1985) Int. J. Tissue React., 7, 137–142.

    CAS  PubMed  Google Scholar 

  25. Curzio, M., Di Mauro, C., Esterbauer, H., and Dianzani, M. U. (1987) Biomed. Pharmacother., 41, 304–314.

    CAS  PubMed  Google Scholar 

  26. Curzio, M., Esterbauer, H., Poli, G., Biasi, F., Cecchini, G., Di Mauro, C., Cappello, N., and Dianzani, M. U. (1987) Int. J. Tissue React., 9, 295–306.

    CAS  PubMed  Google Scholar 

  27. Curzio, M. (1988) Free Radic. Res. Commun., 5, 55–66.

    Article  CAS  PubMed  Google Scholar 

  28. Rossi, M. A., Di Mauro, C., and Dianzani, M. U. (2001) Int. J. Tissue React., 23, 45–50.

    CAS  PubMed  Google Scholar 

  29. Kumagai, T., Matsukawa, N., Kaneko, Y., Kusumi, Y., Mitsumata, M., and Uchida, K. (2004) J. Biol. Chem., 279, 48389–48396.

    Article  CAS  PubMed  Google Scholar 

  30. Trevisani, M., Siemens, J., Materazzi, S., Bautista, D. M., Nassini, R., Campi, B., Imamachi, N., Andre, E., Patacchini, R., Cottrell, G. S., Gatti, R., Basbaum, A. I., Bunnett, N. W., Julius, D., and Geppetti, P. (2007) Proc. Natl. Acad. Sci. USA, 104, 13519–13524.

    Article  CAS  PubMed  Google Scholar 

  31. Lowes, D. A., Thottakam, B. M., Webster, N. R., Murphy, M. P., and Galley, H. F. (2008) Free Radic. Biol. Med., 45, 1559–1565.

    Article  CAS  PubMed  Google Scholar 

  32. Mukherjee, T. K., Mishra, A. K., Mukhopadhyay, S., and Hoidal, J. R. (2007) J. Immunol., 178, 1835–1844.

    CAS  PubMed  Google Scholar 

  33. Lin, S. J., Shyue, S. K., Hung, Y. Y., Chen, Y. H., Ku, H. H., Chen, J. W., Tam, K. B., and Chen, Y. L. (2005) Arterioscler. Thromb. Vasc. Biol., 25, 334–340.

    Article  CAS  PubMed  Google Scholar 

  34. Radomska-Lesniewska, D. M., Sadowska, A. M., van Overveld, F. J., Demkow, U., Zielinski, J., and de Backer, W. A. (2006) J. Physiol. Pharmacol., 57(Suppl. 4), 325–334.

    PubMed  Google Scholar 

  35. Hashimoto, S., Gon, Y., Matsumoto, K., Takeshita, I., and Horie, T. (2001) Br. J. Pharmacol., 132, 270–276.

    Article  CAS  PubMed  Google Scholar 

  36. Takahashi, M., Suzuki, E., Takeda, R., Oba, S., Nishimatsu, H., Kimura, K., Nagano, T., Nagai, R., and Hirata, Y. (2008) Am. J. Physiol. Heart Circ. Physiol., 294, H2879–2888.

    Article  CAS  PubMed  Google Scholar 

  37. Lu, C., Bambang, I. F., Armstrong, J. S., and Whiteman, M. (2008) Diabetes Obes. Metab., 10, 347–349.

    Article  CAS  PubMed  Google Scholar 

  38. Dugina, V., Fontao, L., Chaponnier, C., Vasiliev, J., and Gabbiani, G. (2001) J. Cell Sci., 114, 3285–3296.

    CAS  PubMed  Google Scholar 

  39. Kondo, M., Cubillo, E., Tobiume, K., Shirakihara, T., Fukuda, N., Suzuki, H., Shimizu, K., Takehara, K., Cano, A., Saitoh, M., and Miyazono, K. (2004) Cell Death Differ., 11, 1092–1101.

    Article  CAS  PubMed  Google Scholar 

  40. Gabbiani, G. (2003) J. Pathol., 200, 500–503.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to B. V. Chernyak.

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Published in Russian in Biokhimiya, 2010, Vol. 75, No. 3, pp. 337–345.

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Demianenko, I.A., Vasilieva, T.V., Domnina, L.V. et al. Novel mitochondria-targeted antioxidants, “Skulachev-Ion” derivatives, accelerate dermal wound healing in animals. Biochemistry Moscow 75, 274–280 (2010). https://doi.org/10.1134/S000629791003003X

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  • DOI: https://doi.org/10.1134/S000629791003003X

Key words

  • mitochondria-targeted antioxidants
  • SkQ1
  • myofibroblasts
  • inflammation
  • skin wounds