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Phosphatidylethanolamines Glycation, Oxidation, and Glycoxidation: Effects on Monocyte and Dendritic Cell Stimulation

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Abstract

Lipid glycation is a non-enzymatic reaction between glucose and the free amino group of aminophospholipids, particularly in chronic hyperglycemia. Glycated phosphatidylethanolamine have been found in plasma and atherosclerotic plaques of diabetic patients and was correlated with increased oxidative and inflammatory stress in diabetes. However, the biological roles of glycated lipids are not fully understood. In this study, we evaluated the effect of palmitoyl-oleoyl-phosphatidylethanolamine (POPE) oxidation, glycation, and glycoxidation products on monocyte and myeloid dendritic cell stimulation. Flow cytometry analysis was used to evaluate the capability of each modified PE to induce the expression of different cytokines (IL-1β, IL-6, IL-8, MIP-1β, and TNF-α) in monocytes or myeloid dendritic cells (mDC). Our results showed that PE modifications induced different effect on the stimulation of cells producing cytokines. All PE modifications induced higher frequencies of cytokine-producing cells than basal state. Higher stimulation levels were obtained with glycated POPE, followed by glycoxidized POPE. In contrast, oxidized POPE negatively regulated the frequency of monocytes and mDC producing cytokines, when compared with non-modified POPE. In conclusion, we verified that PE glycation, compared with oxidation and glycation plus oxidation, had higher ability to stimulate monocytes and mDC. Thus detection of increased levels of PE glycation in diabetes could be considered a predictor of a inflammatory state.

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References

  1. Basta, G., Schmidt, A. M., & De Caterina, R. (2004). Advanced glycation end products and vascular inflammation: Implications for accelerated atherosclerosis in diabetes. Cardiovascular Research, 63, 582–592.

    Article  PubMed  CAS  Google Scholar 

  2. Vlassara, H., & Palace, M. R. (2003). Glycoxidation: The menace of diabetes and aging. Mount Sinai Journal of Medicine, 70, 232–241.

    PubMed  Google Scholar 

  3. Breitling-Utzmann, C. M., Unger, A., Friedl, D. A., & Lederer, M. O. (2001). Identification and quantification of phosphatidylethanolamine-derived glucosylamines and aminoketoses from human erythrocytes—influence of glycation products on lipid peroxidation. Archives of Biochemistry and Biophysics, 391, 245–254.

    Article  PubMed  CAS  Google Scholar 

  4. Nakagawa, K., Oak, J. H., Higuchi, O., Tsuzuki, T., Oikawa, S., Otani, H., et al. (2005). Ion-trap tandem mass spectrometric analysis of Amadori-glycated phosphatidylethanolamine in human plasma with or without diabetes. Journal of Lipid Research, 46, 2514–2524.

    Article  PubMed  CAS  Google Scholar 

  5. Ravandi, A., Kuksis, A., Marai, L., Myher, J. J., Steiner, G., Lewisa, G., et al. (1996). Isolation and identification of glycated aminophospholipids from red cells and plasma of diabetic blood. FEBS Letters, 381, 77–81.

    Article  PubMed  CAS  Google Scholar 

  6. Ravandi, A., Kuksis, A., & Shaikh, N. A. (2000). Glucosylated glycerophosphoethanolamines are the major LDL glycation products and increase LDL susceptibility to oxidation: Evidence of their presence in atherosclerotic lesions. Arteriosclerosis Thrombosis and Vascular Biology, 20, 467–477.

    Article  CAS  Google Scholar 

  7. Oak, J., Nakagawa, K., & Miyazawa, T. (2000). Synthetically prepared Aamadori-glycated phosphatidylethanolaminecan trigger lipid peroxidation via free radical reactions. FEBS Letters, 481, 26–30.

    Article  PubMed  CAS  Google Scholar 

  8. Oak, J. H., Nakagawa, K., Oikawa, S., & Miyazawa, T. (2003). Amadori-glycated phosphatidylethanolamine induces angiogenic differentiations in cultured human umbilical vein endothelial cells. FEBS Letters, 555, 419–423.

    Article  PubMed  CAS  Google Scholar 

  9. Simoes, C., Simoes, V., Reis, A., Domingues, P., & Domingues, M. R. (2010). Oxidation of glycated phosphatidylethanolamines: Evidence of oxidation in glycated polar head identified by LC-MS/MS. Analytical and Bioanalytical Chemistry, 397, 2417–2427.

    Article  PubMed  CAS  Google Scholar 

  10. Bochkov, V. N., Oskolkova, O. V., Birukov, K. G., Levonen, A. L., Binder, C. J., & Stockl, J. (2010). Generation and biological activities of oxidized phospholipids. Antioxidants & Redox Signaling, 12, 1009–1059.

    Article  CAS  Google Scholar 

  11. Fruhwirth, G. O., Loidl, A., & Hermetter, A. (2007). Oxidized phospholipids: From molecular properties to disease. Biochimica et Biophysica Acta, 1772, 718–736.

    Article  PubMed  CAS  Google Scholar 

  12. Domingues, M. R., Reis, A., & Domingues, P. (2008). Mass spectrometry analysis of oxidized phospholipids. Chemistry and Physics of Lipids, 156, 1–12.

    Article  PubMed  CAS  Google Scholar 

  13. Watson, A. D., Leitinger, N., Navab, M., Faull, K. F., Horkko, S., Witztum, J. L., et al. (1997). Structural identification by mass spectrometry of oxidized phospholipids in minimally oxidized low density lipoprotein that induce monocyte/endothelial interactions and evidence for their presence in vivo. Journal of Biological Chemistry, 272, 13597–13607.

    Article  PubMed  CAS  Google Scholar 

  14. Subbanagounder, G., Leitinger, N., Schwenke, D. C., Wong, J. W., Lee, H., Rizza, C., et al. (2000). Determinants of bioactivity of oxidized phospholipids. Specific oxidized fatty acyl groups at the sn-2 position. Arteriosclerosis Thrombosis and Vascular Biology, 20, 2248–2254.

    Article  CAS  Google Scholar 

  15. Berliner, J. A., Subbanagounder, G., Leitinger, N., Watson, A. D., & Vora, D. (2001). Evidence for a role of phospholipid oxidation products in atherogenesis. Trends in Cardiovascular Medicine, 11, 142–147.

    Article  PubMed  CAS  Google Scholar 

  16. Leonarduzzi, G., Gamba, P., Gargiulo, S., Biasi, F., & Poli, G. (2012). Inflammation-related gene expression by lipid oxidation-derived products in the progression of atherosclerosis. Free Radical Biology & Medicine, 52, 19–34.

    Article  CAS  Google Scholar 

  17. Jyrkkanen, H. K., Kansanen, E., Inkala, M., Kivela, A. M., Hurttila, H., Heinonen, S. E., et al. (2008). Nrf2 regulates antioxidant gene expression evoked by oxidized phospholipids in endothelial cells and murine arteries in vivo. Circulation Research, 103, e1–e9.

    Article  PubMed  CAS  Google Scholar 

  18. Folch, J., Lees, M., & Sloane Stanley, G. H. (1957). A simple method for the isolation and purification of total lipides from animal tissues. Journal of Biological Chemistry, 226, 497–509.

    PubMed  CAS  Google Scholar 

  19. Spickett, C. M., Pitt, A. R., & Brown, A. J. (1998). Direct observation of lipid hydroperoxides in phospholipid vesicles by electrospray mass spectrometry. Free Radical Biology & Medicine, 25, 613–620.

    Article  CAS  Google Scholar 

  20. Domingues, M. R., Simoes, C., da Costa, J. P., Reis, A., & Domingues, P. (2009). Identification of 1-palmitoyl-2-linoleoyl-phosphatidylethanolamine modifications under oxidative stress conditions by LC-MS/MS. Biomedical Chromatography, 23, 588–601.

    Article  PubMed  CAS  Google Scholar 

  21. Gugiu, B. G., Mesaros, C. A., Sun, M., Gu, X., Crabb, J. W., & Salomon, R. G. (2006). Identification of oxidatively truncated ethanolamine phospholipids in retina and their generation from polyunsaturated phosphatidylethanolamines. Chemical Research in Toxicology, 19, 262–271.

    Article  PubMed  CAS  Google Scholar 

  22. Maskrey, B. H., Bermudez-Fajardo, A., Morgan, A. H., Stewart-Jones, E., Dioszeghy, V., Taylor, G. W., et al. (2007). Activated platelets and monocytes generate four hydroxyphosphatidylethanolamines via lipoxygenase. Journal of Biological Chemistry, 282, 20151–20163.

    Article  PubMed  CAS  Google Scholar 

  23. Reis, A., Domingues, M. R., Amado, F. M., Ferrer-Correia, A. J., & Domingues, P. (2005). Separation of peroxidation products of diacyl-phosphatidylcholines by reversed-phase liquid chromatography-mass spectrometry. Biomedical Chromatography, 19, 129–137.

    Article  PubMed  CAS  Google Scholar 

  24. Pradhan, A. D., Manson, J. E., Rifai, N., Buring, J. E., & Ridker, P. M. (2001). C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA, 286, 327–334.

    Article  PubMed  CAS  Google Scholar 

  25. Esposito, K., Nappo, F., Marfella, R., Giugliano, G., Giugliano, F., Ciotola, M., et al. (2002). Inflammatory cytokine concentrations are acutely increased by hyperglycemia in humans: Role of oxidative stress. Circulation, 106, 2067–2072.

    Article  PubMed  CAS  Google Scholar 

  26. Kado, S., Nagase, T., & Nagata, N. (1999). Circulating levels of interleukin-6, its soluble receptor and interleukin-6/interleukin-6 receptor complexes in patients with type 2 diabetes mellitus. Acta Diabetologica, 36, 67–72.

    Article  PubMed  CAS  Google Scholar 

  27. Shikano, M., Sobajima, H., Yoshikawa, H., Toba, T., Kushimoto, H., Katsumata, H., et al. (2000). Usefulness of a highly sensitive urinary and serum IL-6 assay in patients with diabetic nephropathy. Nephron, 85, 81–85.

    Article  PubMed  CAS  Google Scholar 

  28. Zozulinska, D., Majchrzak, A., Sobieska, M., Wiktorowicz, K., & Wierusz-Wysocka, B. (1999). Serum interleukin-8 level is increased in diabetic patients. Diabetologia, 42, 117–118.

    Article  PubMed  CAS  Google Scholar 

  29. Straczkowski, M., Kowalska, I., Nikolajuk, A., Dzienis-Straczkowska, S., Szelachowska, M., & Kinalska, I. (2003). Plasma interleukin 8 concentrations in obese subjects with impaired glucose tolerance. Cardiovascular Diabetology, 2, 5.

    Article  PubMed  Google Scholar 

  30. Feghali, C. A., & Wright, T. M. (1997). Cytokines in acute and chronic inflammation. Frontiers in Bioscience, 2, d12–d26.

    PubMed  CAS  Google Scholar 

  31. Maurer, M., & von Stebut, E. (2004). Macrophage inflammatory protein-1. International Journal of Biochemistry & Cell Biology, 36, 1882–1886.

    Article  CAS  Google Scholar 

  32. Pickup, J. C., Chusney, G. D., Thomas, S. M., & Burt, D. (2000). Plasma interleukin-6, tumour necrosis factor alpha and blood cytokine production in type 2 diabetes. Life Sciences, 67, 291–300.

    Article  PubMed  CAS  Google Scholar 

  33. Subbanagounder, G., Deng, Y., Borromeo, C., Dooley, A. N., Berliner, J. A., & Salomon, R. G. (2002). Hydroxy alkenal phospholipids regulate inflammatory functions of endothelial cells. Vascular Pharmacology, 38, 201–209.

    Article  PubMed  CAS  Google Scholar 

  34. Gleissner, C. A., Leitinger, N., & Ley, K. (2007). Effects of native and modified low-density lipoproteins on monocyte recruitment in atherosclerosis. Hypertension, 50, 276–283.

    Article  PubMed  CAS  Google Scholar 

  35. Sun, L., Ishida, T., Yasuda, T., Kojima, Y., Honjo, T., Yamamoto, Y., et al. (2009). RAGE mediates oxidized LDL-induced pro-inflammatory effects and atherosclerosis in non-diabetic LDL receptor-deficient mice. Cardiovascular Research, 82, 371–381.

    Article  PubMed  CAS  Google Scholar 

  36. Zimman, A., Chen, S. S., Komisopoulou, E., Titz, B., Martinez-Pinna, R., Kafi, A., et al. (2010). Activation of aortic endothelial cells by oxidized phospholipids: A phosphoproteomic analysis. Journal of Proteome Research, 9, 2812–2824.

    Article  PubMed  CAS  Google Scholar 

  37. Sima, A. V., Botez, G. M., Stancu, C. S., Manea, A., Raicu, M., & Simionescu, M. (2010). Effect of irreversibly glycated LDL in human vascular smooth muscle cells: Lipid loading, oxidative and inflammatory stress. Journal of Cellular and Molecular Medicine, 14, 2790–2802.

    Article  PubMed  CAS  Google Scholar 

  38. Isoda, K., Folco, E., Marwali, M. R., Ohsuzu, F., & Libby, P. (2008). Glycated LDL increases monocyte CC chemokine receptor 2 expression and monocyte chemoattractant protein-1-mediated chemotaxis. Atherosclerosis., 198, 307–312.

    Article  PubMed  CAS  Google Scholar 

  39. Hodgkinson, C. P., Laxton, R. C., Patel, K., & Ye, S. (2008). Advanced glycation end-product of low density lipoprotein activates the toll-like 4 receptor pathway implications for diabetic atherosclerosis. Arteriosclerosis Thrombosis and Vascular Biology, 28, 2275–2281.

    Article  CAS  Google Scholar 

  40. Toma, L., Stancu, C. S., Botez, G. M., Sima, A. V., & Simionescu, M. (2009). Irreversibly glycated LDL induce oxidative and inflammatory state in human endothelial cells; added effect of high glucose. Biochemical and Biophysical Research Communications, 390, 877–882.

    Article  PubMed  CAS  Google Scholar 

  41. Sonoki, K., Yoshinari, M., Iwase, M., Iino, K., Ichikawa, K., Ohdo, S., et al. (2002). Glycoxidized low-density lipoprotein enhances monocyte chemoattractant protein-1 mRNA expression in human umbilical vein endothelial cells: Relation to lysophosphatidylcholine contents and inhibition by nitric oxide donor. Metabolism, 51, 1135–1142.

    Article  PubMed  CAS  Google Scholar 

  42. Pertynska-Marczewska, M., Kiriakidis, S., Wait, R., Beech, J., Feldmann, M., & Paleolog, E. M. (2004). Advanced glycation end products upregulate angiogenic and pro-inflammatory cytokine production in human monocyte/macrophages. Cytokine, 28, 35–47.

    Article  PubMed  CAS  Google Scholar 

  43. Abordo, E. A., & Thornalley, P. J. (1997). Synthesis and secretion of tumour necrosis factor-alpha by human monocytic THP-1 cells and chemotaxis induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. Immunology Letters, 58, 139–147.

    Article  PubMed  CAS  Google Scholar 

  44. Abordo, E. A., Westwood, M. E., & Thornalley, P. J. (1996). Synthesis and secretion of macrophage colony stimulating factor by mature human monocytes and human monocytic THP-1 cells induced by human serum albumin derivatives modified with methylglyoxal and glucose-derived advanced glycation endproducts. Immunology Letters, 53, 7–13.

    Article  PubMed  CAS  Google Scholar 

  45. Berbaum, K., Shanmugam, K., Stuchbury, G., Wiede, F., Korner, H., & Munch, G. (2008). Induction of novel cytokines and chemokines by advanced glycation endproducts determined with a cytometric bead array. Cytokine, 41, 198–203.

    Article  PubMed  CAS  Google Scholar 

  46. Westwood, M. E., & Thornalley, P. J. (1996). Induction of synthesis and secretion of interleukin 1 beta in the human monocytic THP-1 cells by human serum albumins modified with methylglyoxal and advanced glycation endproducts. Immunology Letters, 50, 17–21.

    Article  PubMed  CAS  Google Scholar 

  47. Liu, J., Zhao, S., Tang, J., Li, Z., Zhong, T., Liu, Y., et al. (2009). Advanced glycation end products and lipopolysaccharide synergistically stimulate proinflammatory cytokine/chemokine production in endothelial cells via activation of both mitogen-activated protein kinases and nuclear factor-kappaB. FEBS Journal, 276, 4598–4606.

    Article  PubMed  CAS  Google Scholar 

  48. Morohoshi, M., Fujisawa, K., Uchimura, I., & Numano, F. (1995). The effect of glucose and advanced glycosylation end products on IL-6 production by human monocytes. Annals of the New York Academy of Sciences, 748, 562–570.

    Article  PubMed  CAS  Google Scholar 

  49. Higai, K., Satake, M., Nishioka, H., Azuma, Y., & Matsumoto, K. (2008). Glycated human serum albumin enhances macrophage inflammatory protein-1beta mRNA expression through protein kinase C-delta and NADPH oxidase in macrophage-like differentiated U937 cells. Biochimica et Biophysica Acta, 1780, 307–314.

    Article  PubMed  CAS  Google Scholar 

  50. Ge, J., Jia, Q., Liang, C., Luo, Y., Huang, D., Sun, A., et al. (2005). Advanced glycosylation end products might promote atherosclerosis through inducing the immune maturation of dendritic cells. Arteriosclerosis Thrombosis and Vascular Biology, 25, 2157–2163.

    Article  CAS  Google Scholar 

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Acknowledgments

The authors thank the financial support provided to Cláudia Simões (PhD Grant, SFRH/BD/46293/2008), project PTDC/QUI-BIQ/104968/2008, QOPNA, and RNEM by the Foundation for Science and Technology (FCT).

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Correspondence to M. Rosário M. Domingues.

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Simões, C., Silva, A.C., Domingues, P. et al. Phosphatidylethanolamines Glycation, Oxidation, and Glycoxidation: Effects on Monocyte and Dendritic Cell Stimulation. Cell Biochem Biophys 66, 477–487 (2013). https://doi.org/10.1007/s12013-012-9495-2

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