Share This Article:

Anti eotaxin-2 antibodies attenuate the initiation and progression of experimental atherosclerosis

Full-Text HTML Download Download as PDF (Size:705KB) PP. 339-346
DOI: 10.4236/wjcd.2013.34054    3,138 Downloads   4,608 Views   Citations

ABSTRACT

Background: The chemokine eotaxin-2 is a potent chemoattractant for inflammatory cells, the predominants of which are eosinophils. Human and murine atherosclerotic plaques are known to exhibit inflammatory phenotypes where a complex interaction of cytokine and chemokines plays a role. We tested the hypothesis that eotaxin-2 (eo-2) plays a causative role in the initiation and progression of experimental atherosclerosis. Methods and Results: Sera collected from atherosclerotic ApoE knockout (KO) mice, exhibited significantly higher levels of eo-2 compared to sera collected from their background age matched C57BL/6 litters by ELISA. Moreover, levels of eo-2 were higher in old atherosclerotic ApoE KO mice than in young animals. Similarly, the expression level of the eo-2 receptor, CCR3, was increased in splenocytes of old ApoE compared to the young littermates. Administration of polyclonal blocking antibodies to eotaxin-2 resulted in a significant reduction of early atherosclerotic plaques in ApoE KO mice whereas prolonged treatment of mice with advanced plaques led to atheroma stabilization. A monoclonal antibody (D8) prepared against eo-2 attenuated adhesion of lymphocytes to fibronectin and potently inhibited their migration towards VEGF. Monoclonal blocking antibodies to eo-2 also significantly reduced atherosclerotic plaques in ApoE KO mice. Conclusion: Eo-2 serum levels are elevated in sera of ApoE KO mice with experimental atherosclerosis and its blockade is associated with reduced fatty streak accumulation and increased plaque stabilization.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Mor, A. , Afek, A. , Entin-Meer, M. , Keren, G. and George, J. (2013) Anti eotaxin-2 antibodies attenuate the initiation and progression of experimental atherosclerosis. World Journal of Cardiovascular Diseases, 3, 339-346. doi: 10.4236/wjcd.2013.34054.

References

[1] Jose, P.J., Griffiths-Johnson, D.A., Collins, P.D., Walsh, D.T., Moqbel, R., Totty, N.F., Truong, O., Hsuan, J.J. and Williams, T.J. (1994) Eotaxin: A potent eosinophil chemoattractant cytokine detected in a guinea pig model of allergic airways inflammation. The Journal of Experimental Medicine, 179, 881-887. doi:10.1084/jem.179.3.881
[2] Kitaura, M., Nakajima, T., Imai, T., Harada, S., Combadiere, C., Tiffany, H.L., Murphy, P.M. and Yoshie, O. (1996) Molecular cloning of human eotaxin, an eosinophil-selective CC chemokine, and identification of a specific eosinophil eotaxin receptor, CC chemokine receptor 3. The Journal of Biological Chemistry, 271, 7725-7730. doi:10.1074/jbc.271.13.7725
[3] Ponath, P.D., Qin, S., Ringler, D.J., Clark-Lewis, I., Wang, J., Kassam, N., Smith, H., Shi, X., Gonzalo, J.A., Newman, W., Gutierrez-Ramos, J.C. and Mackay, C.R. (1996) Cloning of the human eosinophil chemoattractant, eotaxin. Expression, receptor binding, and functional properties suggest a mechanism for the selective recruitment of eosinophils. Journal of Clinical Investigation, 97, 604612. doi:10.1172/JCI118456
[4] Pease, J.E. (2006) Asthma, allergy and chemokines. Current Drug Targets, 7, 3-12. doi:10.2174/138945006775270204
[5] Berger, O., Gan, X., Gujuluva, C., Burns, A.R., Sulur, G., Stins, M., Way, D., Witte, M., Weinand, M., Said, J., Kim, K.S., Taub, D., Graves, M.C. and Fiala, M. (1999) CXC and CC chemokine receptors on coronary and brain endothelia. Molecular Medicine, 5, 795-805.
[6] Salcedo, R., Resaum J.H., Halversonm D., Hudsonm E.A., Dambach, M., Powell, D., Wasserman, K. and Oppenheim, J.J. (2000) Differential expression and responsiveness of chemokine receptors (CXCR1-3) by human microvascular endothelial cells and umbilical vein endothelial cells. The FASEB Journal, 14, 2055-2064. doi:10.1096/fj.99-0963com
[7] Romagnani, P., Annunziato, F., Lasagni, L., Lazzeri, E., Beltrame, C., Francalanci, M., Uguccioni, M., Galli, G., Cosmi, L., Maurenzig, L., Baggiolini, M., Maggi, E., Romagnani, S. and Serio, M. (2001) Cell cycle-dependent expression of CXC chemokine receptor 3 by endothelial cells mediates angiostatic activity. Journal of Clinical Investigation, 107, 53-63. doi:10.1172/JCI9775
[8] Salcedo, R., Young, H.A., Ponce, M.L., Ward, J.M., Kleinman, H.K., Murphy, W.J. and Oppenheim, J.J. (2001) Eotaxin (CCL11) induces in vivo angiogenic responses by human CCR3+ endothelial cells. The Journal of Immunology, 166, 7571-7578.
[9] Cheng, S.S., Lukacs, N.W. and Kunkel, S.L. (2002) Eotaxin/CCL11 suppresses IL-8/CXCL8 secretion from human dermal microvascular endothelial cells. The Journal of Immunology, 168, 2887-2894.
[10] Agrawal, L., Maxwell, C.R., Peters, P.J., Clapham, P.R., Liu, S.M., Mackay, C.R. and Strayer, D.S. (2009) Complexity in human immunodeficiency virus type 1 (HIV-1) co-receptor usage: Roles of CCR3 and CCR5 in HIV-1 infection of monocyte-derived macrophages and brain microglia. Journal of General Virology, 90, 710-722. doi:10.1099/vir.0.006205-0
[11] Hansson, G.K. (2005) Inflammation, atherosclerosis, and coronary artery disease. The New England Journal of Medicine, 352, 1685-1695. doi:10.1056/NEJMra043430
[12] Sun, J., Sukhova, G.K., Wolters, P.J., Yang, M., Kitamoto, S., Libby, P., MacFarlane, L.A., Mallen-St Clair, J. and Shi, G.P. (2007) Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nature Medicine, 13, 719-724. doi:10.1038/nm1601
[13] Kodali, R., Hajjou, M., Berman, A.B., Bansal, M.B., Zhang, S., Pan, J.J. and Schecter, A.D. (2006) Chemokines induce matrix metalloproteinase-2 through activation of epidermal growth factor receptor in arterial smooth muscle cells. Cardiovascular Research, 69, 706-715. doi:10.1016/j.cardiores.2005.09.012
[14] Sheikine, Y., Olsen, B., Gharizadeh, B., Jatta, K., Tornvall, P. and Ghaderi, M. (2006) Influence of eotaxin 67G>A polymorphism on plasma eotaxin concentrations in myocardial infarction survivors and healthy controls. Atherosclerosis, 189, 458-463. doi:10.1016/j.atherosclerosis.2006.01.003
[15] Economou, E., Tousoulis, D., Katinioti, A., Stefanadis, C., Trikas, A., Pitsavos, C., Tentolouris, C., Toutouza, M.G. and Toutouzas, P. (2001) Chemokines in patients with ischaemic heart disease and the effect of coronary angioplasty. International Journal of Cardiology, 80, 55-60. doi:10.1016/S0167-5273(01)00454-5
[16] Emanuele, E., Falcone, C., D’Angelo, A., Minoretti, P., Buzzi, M.P., Bertona, M. and Geroldi, D. (2006) Association of plasma eotaxin levels with the presence and extent of angiographic coronary artery disease. Atherosclerosis, 186, 140-145. doi:10.1016/j.atherosclerosis.2005.07.002
[17] Ardigo, D., Assimes, T.L., Fortmann, S.P., Go, A.S., Hlatky, M., Hytopoulos, E., Iribarren, C., Tsao, P.S., Tabibiazar, R., Quertermous, T. and ADVANCE Investigators (2007) Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease. Physiological Genomics, 31, 402-409.
[18] Sheikine, Y.A. and Hansson, G.K. (2006) Chemokines as potential therapeutic targets in atherosclerosis. Current Drug Targets, 7, 13-27. doi:10.2174/138945006775270240
[19] Ablin, J.N., Entin-Meer, M., Aloush, V., Oren, S., Elkayam, O., George, J. and Barshack, I. (2010) Protective effect of eotaxin-2 inhibition in adjuvant-induced arthritis. Clinical & Experimental Immunology, 161, 376-283. doi:10.1111/j.1365-2249.2010.04172.x
[20] Weber, C., Zernecke, A. and Libby, P. (2008) The multifaceted contributions of leukocyte subsets to atherosclerosis: Lessons from mouse models. Nature Reviews Immunology, 8, 802-815. doi:10.1038/nri2415
[21] Bot, I., de Jager, S.C., Zernecke, A., Lindstedt, K.A., van Berkel, T.J., Weber, C. and Biessen, E.A. (2007) Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation, 115, 2516-2525. doi:10.1161/01.ATV.14.9.1480
[22] Haley, K.J., Lilly, C.M., Yang, J.H., Feng, Y., Kennedy, S.P., Turi, T.G., Thompson, J.F., Sukhova, G.H., Libby, P. and Lee, R.T. (2000) Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: Using genomic technology to identify a potential novel pathway of vascular inflammation. Circulation, 102, 2185-2189. doi:10.1161/01.CIR.102.18.2185
[23] Kovanen, P.T. (2007) Mast cells: Multipotent local effector cells in atherothrombosis. Immunological Reviews, 217, 105-122. doi:10.1111/j.1600-065X.2007.00515.x
[24] Boring, L., Gosling, J., Cleary, M. and Charo, I.F. (1998) Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature, 394, 894-897. doi:10.1038/29788
[25] Hillyer, P., Mordelet, E., Flynn, G. and Male, D. (2003) Chemokines, chemokine receptors and adhesion molecules on different human endothelia: Discriminating the tissue-specific functions that affect leucocyte migration. Clinical & Experimental Immunology, 134, 431-441. doi:10.1111/j.1365-2249.2003.02323.x

  
comments powered by Disqus

Copyright © 2018 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.