ABSTRACT Toll-like receptors are well-defined barriers in innate immunity. Among them hTLR4 on the surface of monocytes, plays a critical role in the formation of atherosclerotic plaques, plaque instability and arterial remodeling through production of inflammatory cytokines. This study was designed to examine the association of hTLR4 monocyte expression and response with the severity of coronary stenosis in patients with stable angina (SA). Blood samples were obtained from 39 patients with SA who were scheduled for a coronary angiography and from 28 healthy volunteers. The samples were collected before the procedure. Expression of hTLR4 on CD14+ monocytes and serum levels of TNF-α and IL-1β were measured using flowcytometry and ELISA techniques respectively. Percentage stenosis diameter was measured by comparing the area of coronary stenosis to an adjacent normal segment of the vessel. Compared with control group, patients showed upregulation of hTLR4+/CD14+ monocytes. Furthermore, patients with more severe coronary stenosis exhibited enhanced expression of hTLR4+/CD14+ monocytes (p < 0.01). This was paralleled by elevation in the serum levels of TNF-α (p < 0.05) and IL-1β. In addition, significant correlations were seen between percentage stenosis diameter and monocyte expression of hTLR4 as well as TNF-α. hTLR4 monocytic expression and related cytokines are positively associated percentage stenosis diameter. These results suggest that hTLR4 activity may be involved in progression of atherosclerosis.
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Bagheri, B. , Sohrabi, B. , Movassaghpur, A. , Mashayekhi, S. , Garjani, A. , Shokri, M. , Noori, M. and Garjani, A. (2013) Association of monoctye expression of Toll-like receptor 4 and its related cytokines with coronary luminal stenosis. Advances in Bioscience and Biotechnology, 4, 19-25. doi: 10.4236/abb.2013.47A1004.
 Ross, R. (1999) Atherosclerosis—An inflammatory disease. New England Journal of Medicine, 340, 115-126.
 Glass, C. and Witztum, J. (2001) Atherosclerosis: The road ahead. Cell, 104, 503-516.
 Bennet, M.R. (1999) Apoptosis of vascular smooth muscle cells in vascular remodeling and atherosclerotic plaque rupture. Cardiovascular Research, 41, 361-368.
 Takeda, K. and Akira, S. (2005) Toll-like receptors in innate immunity. International Immunology, 17, 1-14.
 Kaisho, T. and Akira, S. (2006) Molecular mechanisms in allergy and clinical immunology. Journal of Allergy and Clinical Immunology, 117, 979-987.
 Vink, A., Schoneveld, H.A., Van der Meer, J., et al. (2001) In vivo evidence for a role of Toll-like receptor 4 in the development of intimal lesions. Circulation, 104, 3103-3108.
 Fishbein, M., Luthringer, D., Xu, X., et al. (2001) Tolllike receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation, 104, 3103-3108.
 McDermott, E. and O’Neill, L. (2004) Signal transduction by the lipopolysaccharide receptor, Toll-like recaptor-4. Journal of Immunology, 113, 153-162.
 Tsan, M. and Gao, B. (2004) Endogenous ligands of Tolllike receptors. Journal of Leukocyte Biology, 76, 514-519.
 Ohashi, K., Burkart, V., Flohé, S. and Kolb, H. (2000) Cutting edge: Heat shock protein 60 is a putative endogenous ligand of the Toll-like receptor-4 complex. Journal of Immunology, 164, 558-561.
 Miller, Y., Viriyakoso, S., Binder, C., Feramisco, J., Kirkland, T. and Witztum, J. (2003) Minimally modified LDL binds to CD14, induces macrophage spreading via TLR4/MD-2, and inhibits phagocytosis of apoptotic cells. Journal of Biological Chemistry, 278, 1561-1568.
 Schnare, M., Barton, G., Holt, A., Takeda, K., Akira, S. and Medzhitov, R. (2001) Toll-like receptors control activation of adaptive immune responses. Nature Immunology, 41, 947-950. doi:10.1038/ni712
 Frantz, S. and Bauersachs, J. (2010) Toll-like receptors: Emerging therapeutic targets for heart failure. Heart and Metabolism, 47, 19-22.
 Methe, H., Kim, J., Kofler, S., Weis, M., Nabauer, M. and Koglin, J. (2005) Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation, 111, 2654-2661.
 Irwin, M.W., Mak, S., Mann, D.L., et al. (1999) Tissue expression and immunolocalization of tumor necrosis factor-α in post infarction dysfunctional myocardium. Circulation, 99, 1492-1498.
 Dinarello, C.A. and Wolff, S. (1993) The role of interleukin-1 in disease. New England Journal of Medicine, 328, 106-112. doi:10.1056/NEJM199301143280207
 Kim, C. M., Kini, A. and Sharma, K.S. (2002) Refractory angina pectoris: Mechanism and therapeutic options. Journal of the American College of Cardiology, 39, 923-934.
 Abrams, J. (2005) Chronic stable angina. New England Journal of Medicine, 352, 2524-2533.
 Hollestelle, S.C., De Vries, R.M., Van Keulen, J.K., et al. (2004) Toll-like receptor 4 is involved in outward arterial remodeling. Circulation, 109, 393-398.
 Pasterkamp, G., Schoneveld, H.A., Van Derwal, A., et al. (1998) Relation of arterial geometry to luminal narrowing and histologic markers for plaque vulnerability: The remodeling paradox. Journal of the American College of Cardiology, 32, 655-662.
 Ameziane, N., Beillat, T., Verpilla, P., et al. (2003) Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, e61-e64.
 Medvedev, E.A., Kopydlowski, K.M. and Vogel, N.S. (2000) Inhibition of lipopolysaccharide-induced signal transduction in endotoxin-tolerized mouse macrophages: Dysregulation of cytokine, chemokine, and Toll-like receptor 2 and 4 gene expression. Journal of Immunology, 164, 5564-5574.
 Takeshita, F., Tanaka, T., Matsuda, T., et al. (2006) TollLike Receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of Innate Immunity. Journal of Virology, 80, 6218-6224. doi:10.1128/JVI.00121-06
 Methe, H., Brunner, S., Wiegand, D., Nabauer, M. and Koglin, J. (2005) Enhanced T-Helper-1 lymphocyte activation patterns in acute coronary syndromes. Journal of the American College of Cardiology, 45, 1939-1945.
 Versteeg, D., Hoefer, I.E., Schoneveld, A.H., et al. (2008) Monocyte Toll-Like Receptor 2 and 4 response and expression following percutaneous coronary intervention: Association between lesion stenosis and fractional flow reserve. Heart, 94, 770-776. doi:10.1136/hrt.2007.117259
 Akira, S. and Hemmi, H. (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunology Letters, 85, 85-95.
 Yang, J. and Ding, J. (2008) Sequential expression of TLR4 and its effects on the myocardium of rats with myocardial ischemia-reperfusion injury. Inflammation, 31, 304-312. doi:10.1007/s10753-008-9079-x
 Bjorkbacka, H., Kunjathoor, V., Moore, K., et al. (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways. Nature Medicine, 10, 416421. doi:10.1038/nm1008
 Michelsen, K., Kathrin, S., Wong, M., et al. (2004) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E. Proceedings of the National Academy of Sciences of the United States of America, 101, 10679-10684.
 Shimamoto, A., Chong, A., Yada, M., et al. (2006) Inhibition of Toll-like receptor 4 with eritoran attenuates myocardial ischemia-reperfusion injury. Circulation, 114, 270-274. doi:10.1161/CIRCULATIONAHA.105.000901
 Schoenhagen, P., Ziada, K.M., Kapadia, R.S., Crowe, D.T., Nissen, E.S. and Tuzcu, E.M. (2000) Extent and direction of arterial remodeling in stable versus unstable coronary syndromes. Circulation, 101, 598-603.
 Bagheri, B., Sohrabi, B., Movassaghpour, A., et al. (2012) Monocyte expression of toll-like receptor-4 in patients with stable angina undergoing percutanoeus coronary intervention. Iranian Journal of Immunology, 9, 149-158.
 Ikonomidis, I., Andreotti, F., Economou, E., Stefanadis, C., Toutouzas, P. and Nihoyannopoulos, P. (1999) Increased proinflammatory cytokines in patients with chronic stable angina and their reduction by aspirin. Circulation, 100, 793-798. doi:10.1161/01.CIR.100.8.793
 Bhagat, K. and Vallance, P. (1997) Inflammatory cytokines impair endothelial dependent dilatation in human veins in vivo. Circulation, 96, 3042-3047.
 Hansson, G.K., Libby, P., Schonbeck, U. and Yan, Z.Q. (2002) Innate and adaptive immunity in the pathogenesis of atherosclerosis. Circulation Research, 91, 281-291.
 Iechl, S., Lorenz, E., Reindl, M., et al. (2002) Toll-like receptor 4 polymorphisms and atherogenesis. New England Journal of Medicine, 347, 185-192.
 Heil, M. and Schaper, W. (2004) Influence of mechanical, cellular, and molecular factors on collateral artery. Circulation Research, 95, 449-458.
 Deindl, E. and Schaper, W. (2005) The art of arteriogenesis. Cell Biochemistry and Biophysics, 43, 1-15.
 Hoefer, I.E., Van, R.N. and Rectenwald, J.E. (2002) Direct evidence for tumor necrosis factor-alpha signaling in arteriogenesis. Circulation, 105, 1639-1641.
 Yoshida, J., Ohmori, K. and Takeuchi, H. (2005) Treatment of ischemic limbs on local recruitment of vascular endothelial growth factor-producing inflammatory cells with ultrasonic microbubble destruction. Journal of the American College of Cardiology, 46, 899-905.
 Grote, K., Schütt, H. and Schieffer, B. (2011) Toll-like receptors in angiogenesis. Science World Journal, 11, 981-991. doi:10.1100/tsw.2011.92
 Methe, H., Kim, J., Kofler, S., Weis, M., Nabauer, M. and Koglin, J. (2005) Statins decrease Toll-like receptor 4 expression and downstream signaling in human CD14+ monocytes. Circulation, 25, 1439-1445.
 Moutzouri, E., Tellis, C., Rousouli, K., et al. (2012) Effect of simvastatin or its combination with ezetimibe on Toll-like receptor expression and lipopolysaccharide-induced cytokine production in monocytes of hypercholesterolemic patients. Atherosclerosis, 225, 381-387.