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Vitamin E Induces Phosphatidylserine Externalization and Red Cell Adhesion to Endothelial Cells

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Abstract

Red blood cell (RBC) adhesion to vessel wall endothelium is a potent catalyst of vascular occlusion and occurs in oxidative stress states such as hemoglobinopathies and cardiovascular conditions. These are often treated with vitamin E (VitE), a “classic” antioxidant. In this study, we examined the effects of VitE on RBC adhesion to vascular endothelial cells (EC), and on translocation of phosphatidylserine (PS) to RBC surface, known as a potent mediator of RBC/EC adhesion, facilitating thrombus formation. Treatment of RBC with VitE strongly induces (up to sevenfold) PS externalization and enhances (up to 20-fold) their adherence to EC. The VitE hydrophilic analogue—Trolox—does not incorporate into cell membranes. Trolox did not exhibit any of these effects, implying that the VitE effect is due to its known ability to incorporate into cell membranes. The membrane-incorporated VitE significantly reduced the level of reactive oxygen species in H2O2-treated RBC, demonstrating that VitE elevates RBC/EC adhesion despite acting as an anti-oxidant. This study demonstrates for the first time that contrary to the common view of VitE as a beneficial supplement, VitE may introduce a circulatory risk by inducing flow-disturbing RBC adherence to blood vessel wall and the pro-thrombotic PS exposure.

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References

  1. Barshtein, G., Ben-Ami, R., & Yedgar, S. (2007). Role of red blood cell flow behavior in hemodynamics and hemostasis. Expert Review of Cardiovascular Therapy, 5, 743–752.

    Article  PubMed  Google Scholar 

  2. Porat, R. M., Grunewald, M., Globerman, A., et al. (2004). Specific induction of tie1 promoter by disturbed flow in atherosclerosis-prone vascular niches and flow-obstructing pathologies. Circulation Research, 94, 394–401.

    Article  CAS  PubMed  Google Scholar 

  3. Kaul, D. K., Koshkaryev, A., Artmann, G., Barshtein, G., & Yedgar, S. (2008). Additive effect of red blood cell rigidity and adherence to endothelial cells in inducing vascular resistance. American Journal of Physiology Heart and Circulatory Physiology, 295, H1788–1793.

    Article  CAS  PubMed  Google Scholar 

  4. Kaul, D. K., & Fabry, M. E. (2004). In vivo studies of sickle red blood cells. Microcirculation, 11, 153–165.

    CAS  PubMed  Google Scholar 

  5. Fabry, M. E., Kaul, D. K., Davis, L., Gore, J. C., Brown, M., & Nagel, R. L. (1987). An animal model for sickle cell vaso-occlusion: A study using NMR and technetium imaging. Progress in Clinical and Biological Research, 240, 297–304.

    CAS  PubMed  Google Scholar 

  6. Hebbel, R. P. (2000). Blockade of adhesion of sickle cells to endothelium by monoclonal antibodies. New England Journal of Medicine, 342, 1910–1912.

    Article  CAS  PubMed  Google Scholar 

  7. Yedgar, S., Kaul, D. K., & Barshtein, G. (2008). RBC adhesion to vascular endothelial cells: More potent than RBC aggregation in inducing circulatory disorders. Microcirculation, 15, 581–583.

    Article  PubMed  Google Scholar 

  8. Elion, J. E., Brun, M., Odievre, M. H., Lapoumeroulie, C. L., & Krishnamoorthy, R. (2004). Vaso-occlusion in sickle cell anemia: Role of interactions between blood cells and endothelium. Hematology Journal, 5(Suppl 3), S195–S198.

    Article  PubMed  Google Scholar 

  9. French, J. A., I. I., Kenny, D., Scott, J. P., et al. (1997). Mechanisms of stroke in sickle cell disease: Sickle erythrocytes decrease cerebral blood flow in rats after nitric oxide synthase inhibition. Blood, 89, 4591–4599.

    CAS  PubMed  Google Scholar 

  10. Beeson, J. G., & Brown, G. V. (2002). Pathogenesis of plasmodium falciparum malaria: The roles of parasite adhesion and antigenic variation. Cellular and Molecular Life Sciences, 59, 258–271.

    Article  CAS  PubMed  Google Scholar 

  11. Beeson, J. G., Rogerson, S. J., Cooke, B. M., et al. (2000). Adhesion of plasmodium falciparum-infected erythrocytes to hyaluronic acid in placental malaria. Nature Medicine, 6, 86–90.

    Article  CAS  PubMed  Google Scholar 

  12. Gaziano, J. M. (2004). Vitamin E and cardiovascular disease: Observational studies. Annals of the New York Academy of Sciences, 1031, 280–291.

    Article  CAS  PubMed  Google Scholar 

  13. Singh, U., Devaraj, S., & Jialal, I. (2005). Vitamin E, oxidative stress, and inflammation. Annual Review of Nutrition, 25, 151–174.

    Article  CAS  PubMed  Google Scholar 

  14. Klein, A., Deckert, V., Schneider, M., et al. (2006). Alpha-tocopherol modulates phosphatidylserine externalization in erythrocytes: Relevance in phospholipid transfer protein-deficient mice. Arteriosclerosis, Thrombosis, and Vascular Biology, 26, 2160–2167.

    Article  CAS  PubMed  Google Scholar 

  15. Ramot, Y., Koshkaryev, A., Goldfarb, A., Yedgar, S., & Barshtein, G. (2008). Phenylhydrazine as a partial model for beta-thalassaemia red blood cell hemodynamic properties. British Journal Haematology, 140, 692–700.

    Article  CAS  Google Scholar 

  16. Koshkaryev, A., Zelig, O., Manny, N., Yedgar, S., & Barshtein, G. (2009). Rejuvenation treatment of stored red blood cells reverses storage-induced adhesion to vascular endothelial cells. Transfusion, 49, 2136–2143.

    Article  CAS  PubMed  Google Scholar 

  17. Sanchez-Migallon, M. P., Aranda, F. J., & Gomez-Fernandez, J. C. (1996). The interaction of alpha-tocopherol with phosphatidylserine vesicles and calcium. Biochimica et Biophysica Acta, 1281, 23–30.

    Article  PubMed  Google Scholar 

  18. Sanchez-Migallon, M. P., Aranda, F. J., & Gomez-Fernandez, J. C. (1996). Interaction between alpha-tocopherol and heteroacid phosphatidylcholines with different amounts of unsaturation. Biochimica et Biophysica Acta, 1279, 251–258.

    Article  PubMed  Google Scholar 

  19. Stillwell, W., Ehringer, W., & Wassall, S. R. (1992). Interaction of alpha-tocopherol with fatty acids in membranes and ethanol. Biochimica et Biophysica Acta, 1105, 237–244.

    Article  CAS  PubMed  Google Scholar 

  20. Relevy, H., Koshkaryev, A., Manny, N., Yedgar, S., & Barshtein, G. (2008). Blood banking-induced alteration of red blood cell flow properties. Transfusion, 48, 136–146.

    PubMed  Google Scholar 

  21. Cruz Silva, M. M., Madeira, V. M., Almeida, L. M., & Custodio, J. B. (2001). Hydroxytamoxifen interaction with human erythrocyte membrane and induction of permeabilization and subsequent hemolysis. Toxicology In Vitro, 15, 615–622.

    Article  CAS  PubMed  Google Scholar 

  22. Wang, F., Wang, T., Lai, J., Li, M., & Zou, C. (2006). Vitamin E inhibits hemolysis induced by hemin as a membrane stabilizer. Biochemical Pharmacology, 71, 799–805.

    Article  CAS  PubMed  Google Scholar 

  23. Zingg, J. M., & Azzi, A. (2004). Non-antioxidant activities of vitamin E. Current Medicinal Chemistry, 11, 1113–1133.

    CAS  PubMed  Google Scholar 

  24. Urano, S., Inomori, Y., Sugawara, T., et al. (1992). Vitamin E: Inhibition of retinol-induced hemolysis and membrane-stabilizing behavior. Journal of Biological Chemistry, 267, 18365–18370.

    CAS  PubMed  Google Scholar 

  25. Yoshida, Y., Niki, E., & Noguchi, N. (2003). Comparative study on the action of tocopherols and tocotrienols as antioxidant: Chemical and physical effects. Chemistry and Physics of Lipids, 123, 63–75.

    Article  CAS  PubMed  Google Scholar 

  26. Dyatlov, V. A., Makovetskaia, V. V., Leonhardt, R., Lawrence, D. A., & Carpenter, D. O. (1998). Vitamin E enhances Ca(2+)-mediated vulnerability of immature cerebellar granule cells to ischemia. Free Radical Biology and Medicine, 25, 793–802.

    Article  CAS  PubMed  Google Scholar 

  27. Lang, K. S., Lang, P. A., Bauer, C., et al. (2005). Mechanisms of suicidal erythrocyte death. Cellular Physiology and Biochemistry, 15, 195–202.

    Article  CAS  PubMed  Google Scholar 

  28. Ahkong, Q. F., Fisher, D., Tampion, W., & Lucy, J. A. (1973). The fusion of erythrocytes by fatty acids, esters, retinol and alpha-tocopherol. Biochemical Journal, 136, 147–155.

    CAS  PubMed  Google Scholar 

  29. Ingraham, L. M., Burns, C. P., Boxer, L. A., Baehner, R. L., & Haak, R. A. (1981). Fluidity properties and liquid composition of erythrocyte membranes in Chediak-Higashi syndrome. Journal of Cell Biology, 89, 510–516.

    Article  CAS  PubMed  Google Scholar 

  30. Ivanov, I. T. (2007). Allometric dependence of the life span of mammal erythrocytes on thermal stability and sphingomyelin content of plasma membranes. Comparative Biochemistry and Physiology A: Molecular & Integrative Physiology, 147, 876–884.

    Article  Google Scholar 

  31. Zwaal, R. F., Comfurius, P., & Bevers, E. M. (2005). Surface exposure of phosphatidylserine in pathological cells. Cellular and Molecular Life Sciences, 62, 971–988.

    Article  CAS  PubMed  Google Scholar 

  32. Grisaru, D., Zwang, E., Peyser, M. R., Lessing, J. B., & Eldor, A. (1997). The procoagulant activity of red blood cells from patients with severe preeclampsia. American Journal of Obstetrics and Gynecology, 177, 1513–1516.

    Article  CAS  PubMed  Google Scholar 

  33. Lonn, E., Bosch, J., Yusuf, S., et al. (2005). Effects of long-term vitamin E supplementation on cardiovascular events and cancer: A randomized controlled trial. JAMA, 293, 1338–1347.

    Article  PubMed  Google Scholar 

  34. Miller, E. R., III, Pastor-Barriuso, R., Dalal, D., Riemersma, R. A., Appel, L. J., & Guallar, E. (2005). Meta-analysis: High-dosage vitamin E supplementation may increase all-cause mortality. Annals of Internal Medicine, 2, 37–46.

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Acknowledgments

This study was supported by grants from the US National Blood Foundation (American Association of Blood Banking, to S.Y. and G.B.), the Israel Ministry of Health (to S.Y.), the Israel Science Foundation (No. 558/03 to S.Y. and G.B.), the US-Israel BSF (to S.Y. and G.B.), and the Walter and Greta Stiel Chair for Heart Studies (S.Y.). The authors thank Mrs. O. Fredman for her technical assistance.

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  1. Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel

    Alexander Koshkaryev, Gregory Barshtein & Saul Yedgar

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  1. Alexander Koshkaryev
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  2. Gregory Barshtein
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  3. Saul Yedgar
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Correspondence to Gregory Barshtein.

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Koshkaryev, A., Barshtein, G. & Yedgar, S. Vitamin E Induces Phosphatidylserine Externalization and Red Cell Adhesion to Endothelial Cells. Cell Biochem Biophys 56, 109–114 (2010). https://doi.org/10.1007/s12013-009-9074-3

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