Biochemistry (Moscow)

, Volume 79, Issue 2, pp 124–130 | Cite as

Mitochondria-targeted antioxidants prevent TNFα-induced endothelial cell damage

  • I. I. Galkin
  • O. Yu. Pletjushkina
  • R. A. Zinovkin
  • V. V. Zakharova
  • I. S. Birjukov
  • B. V. Chernyak
  • E. N. Popova
Article

Abstract

Increased serum level of tumor necrosis factor α (TNFα) causes endothelial dysfunction and leads to serious vascular pathologies. TNFα signaling is known to involve reactive oxygen species (ROS). Using mitochondria-targeted antioxidant SkQR1, we studied the role of mitochondrial ROS in TNFα-induced apoptosis of human endothelial cell line EAhy926. We found that 0.2 nM SkQR1 prevents TNFα-induced apoptosis. SkQR1 has no influence on TNFα-dependent proteolytic activation of caspase-8 and Bid, but it inhibits cytochrome c release from mitochondria and cleavage of caspase-3 and its substrate PARP. SkQ analogs lacking the antioxidant moieties do not prevent TNFα-induced apoptosis. The antiapoptotic action of SkQR1 may be related to other observations made in these experiments, namely SkQR1-induced increase in Bcl-2 and corresponding decrease in Bax as well as p53. These results indicate that mitochondrial ROS production is involved in TNFα-initiated endothelial cell death, and they suggest the potential of mitochondria-targeted antioxidants as vasoprotectors.

Key words

endothelium apoptosis mitochondria-targeted antioxidant inflammation TNFα 

Abbreviations

C12R1

rhodamine 19 dodecyl ester

C12TPP

dodecyltriphenylphosphonium

NAC

N-acetylcysteine

PARP

poly(ADP-ribose) polymerase

ROS

reactive oxygen species

SkQs

conjugates of plastoquinone and penetrating cations

SkQ1

plastoquinonyl-10(6′-decyltriphenyl)phosphonium

SkQR1

10-(6′-plastoquinonyl)decylrhodamine 19

TMRM

tetramethylrhodamine methyl ester

TNFα

tumor necrosis factor α

zVAD

N-benzyloxycarbonyl-Val-Ala-Asptrifluoromethyl ketone

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References

  1. 1.
    Pober, J. S., Min, W., and Bradley, J. R. (2009) Annu. Rev. Pathol., 4, 71–95.PubMedCrossRefGoogle Scholar
  2. 2.
    Verrier, E. D., and Boyle, E. M., Jr. (1996) Ann. Thorac. Surg., 62, 915–922.PubMedCrossRefGoogle Scholar
  3. 3.
    Winn, R. K., and Harlan, J. M. (2005) J. Thromb. Haemost., 3, 1815–1824.PubMedCrossRefGoogle Scholar
  4. 4.
    Tham, D. M., Martin-McNulty, B., Wang, Y. X., Wilson, D. W., Vergona, R., Sullivan, M. E., Dole, W., and Rutledge, J. C. (2002) Physiol. Genom., 11, 21–30.Google Scholar
  5. 5.
    Zhang, H., Park, Y., Wu, J., Chen, X., Lee, S., Yang, J., Dellsperger, K. C., and Zhang, C. (2009) Clin. Sci. (Lond.), 116, 219–230.CrossRefGoogle Scholar
  6. 6.
    Madge, L. A., and Pober, J. S. (2001) Exp. Mol. Pathol., 70, 317–325.PubMedCrossRefGoogle Scholar
  7. 7.
    Wajant, H., Pfizenmaier, K., and Scheurich, P. (2003) Cell Death Differ., 10, 45–65.PubMedCrossRefGoogle Scholar
  8. 8.
    Wang, L., Du, F., and Wang, X. (2008) Cell, 133, 693–703.PubMedCrossRefGoogle Scholar
  9. 9.
    Walter, D. H., Haendeler, J., Galle, J., Zeiher, A. M., and Dimmeler, S. (1998) Circulation, 98, 1153–1157.PubMedCrossRefGoogle Scholar
  10. 10.
    Goossens, V., De Vos, K., Vercammen, D., Steemans, M., Vancompernolle, K., Fiers, W., Vandenabeele, P., and Grooten, J. (1999) Biofactors, 10, 145–156.PubMedCrossRefGoogle Scholar
  11. 11.
    Li, J. J., Oberley, L. W., Fan, M., and Colburn, N. H. (1998) FASEB J., 12, 1713–1723.PubMedGoogle Scholar
  12. 12.
    Zhao, Y., Kiningham, K. K., Lin, S. M., and St Clair, D. K. (2001) Antioxid. Redox Signal., 3, 375–386.PubMedCrossRefGoogle Scholar
  13. 13.
    Skulachev, V. P., Antonenko, Y. N., Cherepanov, D. A., Chernyak, B. V., Izyumov, D. S., Khailova, L. S., Klishin, S. S., Korshunova, G. A., Lyamzaev, K. G., Pletjushkina, O. Y., Roginsky, V. A., Rokitskaya, T. I., Severin, F. F., Severina, I. I., Simonyan, R. A., Skulachev, M. V., Sumbatyan, N. V., Sukhanova, E. I., Tashlitsky, V. N., Trendeleva, T. A., Vyssokikh, M. Y., and Zvyagilskaya, R. A. (2010) Biochim. Biophys. Acta, 1797, 878–889.PubMedCrossRefGoogle Scholar
  14. 14.
    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.PubMedCrossRefGoogle Scholar
  15. 15.
    Pletjushkina, O. Y., Lyamzaev, K. G., Popova, E. N., Nepryakhina, O. K., Ivanova, O. Y., Domnina, L. V., Chernyak, B. V., and Skulachev, V. P. (2006) Biochim. Biophys. Acta, 1757, 518–524.PubMedCrossRefGoogle Scholar
  16. 16.
    Popova, E. N., Pletjushkina, O. Y., Dugina, V. B., Domnina, L. V., Ivanova, O. Y., Izyumov, D. S., Skulachev, V. P., and Chernyak, B. V. (2010) Antioxid. Redox Signal., 13, 1297–1307.PubMedCrossRefGoogle Scholar
  17. 17.
    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.CrossRefGoogle Scholar
  18. 18.
    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.CrossRefGoogle Scholar
  19. 19.
    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) Biochemistry (Moscow), 75, 145–150.CrossRefGoogle Scholar
  20. 20.
    Edgell, C. J., McDonald, C. C., and Graham, J. B. (1983) Proc. Natl. Acad. Sci. USA, 80, 3734–3737.PubMedCrossRefGoogle Scholar
  21. 21.
    Lyamzaev, K. G., Pustovidko, A. V., Simonyan, R. A., Rokitskaya, T. I., Domnina, L. V., Ivanova, O. Y., Severina, I. I., Sumbatyan, N. V., Korshunova, G. A., Tashlitsky, V. N., Roginsky, V. A., Antonenko, Y. N., Skulachev, M. V., Chernyak, B. V., and Skulachev, V. P. (2011) Pharm. Res., 28, 2883–2895.PubMedCrossRefGoogle Scholar
  22. 22.
    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.CrossRefGoogle Scholar
  23. 23.
    Ethell, D. W., and Green, D. R. (2002) in Apoptosis Techniques and Protocols (LeBlanc, A., ed.) Springer, New York, pp. 21–34.Google Scholar
  24. 24.
    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.PubMedCrossRefGoogle Scholar
  25. 25.
    Ahn, K., Pan, S., Beningo, K., and Hupe, D. (1995) Life Sci., 56, 2331–2341.PubMedCrossRefGoogle Scholar
  26. 26.
    Polunovsky, V. A., Wendt, C. H., Ingbar, D. H., Peterson, M. S., and Bitterman, P. B. (1994) Exp. Cell Res., 214, 584–594.PubMedCrossRefGoogle Scholar
  27. 27.
    Ohmori, Y., Schreiber, R. D., and Hamilton, T. A. (1997) J. Biol. Chem., 272, 14899–14907.PubMedCrossRefGoogle Scholar
  28. 28.
    Luo, T., and Xia, Z. (2006) Anesth. Analg., 103, 110–116, table of contents.PubMedCrossRefGoogle Scholar
  29. 29.
    Woo, C. H., Eom, Y. W., Yoo, M. H., You, H. J., Han, H. J., Song, W. K., Yoo, Y. J., Chun, J. S., and Kim, J. H. (2000) J. Biol. Chem., 275, 32357–32362.PubMedCrossRefGoogle Scholar
  30. 30.
    Corda, S., Laplace, C., Vicaut, E., and Duranteau, J. (2001) Am. J. Respir. Cell Mol. Biol., 24, 762–768.PubMedCrossRefGoogle Scholar
  31. 31.
    Deshpande, S. S., Angkeow, P., Huang, J., Ozaki, M., and Irani, K. (2000) FASEB J., 14, 1705–1714.PubMedCrossRefGoogle Scholar
  32. 32.
    Martin, D. A., Siegel, R. M., Zheng, L., and Lenardo, M. J. (1998) J. Biol. Chem., 273, 4345–4349.PubMedCrossRefGoogle Scholar
  33. 33.
    Luo, X., Budihardjo, I., Zou, H., Slaughter, C., and Wang, X. (1998) Cell, 94, 481–490.PubMedCrossRefGoogle Scholar
  34. 34.
    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.PubMedCrossRefGoogle Scholar
  35. 35.
    Tuominen, E. K., Wallace, C. J., and Kinnunen, P. K. (2002) J. Biol. Chem., 277, 8822–8826.PubMedCrossRefGoogle Scholar
  36. 36.
    Choi, S. Y., Gonzalvez, F., Jenkins, G. M., Slomianny, C., Chretien, D., Arnoult, D., Petit, P. X., and Frohman, M. A. (2007) Cell Death Differ., 14, 597–606.PubMedCrossRefGoogle Scholar
  37. 37.
    Kagan, V. E., Tyurin, V. A., Jiang, J., Tyurina, Y. Y., Ritov, V. B., Amoscato, A. A., Osipov, A. N., Belikova, N. A., Kapralov, A. A., Kini, V., Vlasova, I. I., Zhao, Q., Zou, M., Di, P., Svistunenko, D. A., Kurnikov, I. V., and Borisenko, G. G. (2005) Nat. Chem. Biol., 1, 223–232.PubMedCrossRefGoogle Scholar
  38. 38.
    Izyumov, D. S., Domnina, L. V., Nepryakhina, O. K., Avetisyan, A. V., Golyshev, S. A., Ivanova, O. Y., Korotetskaya, M. V., Lyamzaev, K. G., Pletjushkina, O. Y., Popova, E. N., and Chernyak, B. V. (2010) Biochemistry (Moscow), 75, 123–129.CrossRefGoogle Scholar
  39. 39.
    Kuznetsov, A. V., and Margreiter, R. (2009) Int. J. Mol. Sci., 10, 1911–1929.PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Thomenius, M. J., and Distelhorst, C. W. (2003) J. Cell Sci., 116, 4493–4499.PubMedCrossRefGoogle Scholar
  41. 41.
    Li, D., Ueta, E., Kimura, T., Yamamoto, T., and Osaki, T. (2004) Cancer Sci., 95, 644–650.PubMedCrossRefGoogle Scholar
  42. 42.
    Luanpitpong, S., Chanvorachote, P., Nimmannit, U., Leonard, S. S., Stehlik, C., Wang, L., and Rojanasakul, Y. (2012) Biochem. Pharmacol., 83, 1643–1654.PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Nakamura, T., and Sakamoto, K. (2001) Biochem. Biophys. Res. Commun., 284, 203–210.PubMedCrossRefGoogle Scholar
  44. 44.
    Aoki, M., Nata, T., Morishita, R., Matsushita, H., Nakagami, H., Yamamoto, K., Yamazaki, K., Nakabayashi, M., Ogihara, T., and Kaneda, Y. (2001) Hypertension, 38, 48–55.PubMedCrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2014

Authors and Affiliations

  • I. I. Galkin
    • 1
    • 2
  • O. Yu. Pletjushkina
    • 1
    • 3
  • R. A. Zinovkin
    • 2
    • 3
  • V. V. Zakharova
    • 3
    • 4
  • I. S. Birjukov
    • 4
  • B. V. Chernyak
    • 1
    • 3
  • E. N. Popova
    • 1
    • 3
  1. 1.Belozersky Institute of Physico-Chemical BiologyLomonosov Moscow State UniversityMoscowRussia
  2. 2.Biological FacultyLomonosov Moscow State UniversityMoscowRussia
  3. 3.Institute of MitoengineeringLomonosov Moscow State UniversityMoscowRussia
  4. 4.Faculty of Bioengineering and BioinformaticsLomonosov Moscow State UniversityMoscowRussia

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