RSS-Feed abonnieren
DOI: 10.1055/s-0030-1257054
© Georg Thieme Verlag KG Stuttgart · New York
Bedeutung von Chemokinen in der Atherogenese
Publikationsverlauf
Publikationsdatum:
02. Februar 2012 (online)
![](https://www.thieme-connect.de/media/kardiologie-u2d/201104/lookinside/thumbnails/10.1055-s-0030-1257054-1.jpg)
Abstract
The accumulation of monocyte-derived macrophages in the arterial wall is crucial for the development of atherosclerotic plaques. Chemokines direct many aspects of the atherogenic monocyte recruitment, such as the peripheral monocyte count, the adhesion and transendothelial migration of monocytes, and the survival of plaque macrophages. Therefore, chemokines and its receptors are promising targets in the treatment of atherosclerosis. However, despite the availability of numerous compounds which target chemokines or chemokine receptors, clinical trials which study the effect of these pharmaceuticals on atherosclerosis in patients are currently missing.
Literatur
- 1 Combadiere C, Potteaux S, Rodero M et al. Combined inhibition of ccl2, cx3cr1, and ccr5 abrogates ly6c(hi) and ly6c(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008; 117 1649-1657
- 2 Takeya M, Yoshimura T, Leonard E J, Takahashi K. Detection of monocyte chemoattractant protein-1 in human atherosclerotic lesions by an anti-monocyte chemoattractant protein-1 monoclonal antibody. Hum Pathol. 1993; 24 534-539
- 3 Nelken N A, Coughlin S R, Gordon D, Wilcox J N. Monocyte chemoattractant protein-1 in human atheromatous plaques. J Clin Invest. 1991; 88 1121-1127
- 4 Ylä-Herttuala S, Lipton B A, Rosenfeld M E et al. Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions. Proc Natl Acad Sci USA. 1991; 88 5252-5256
- 5 Cushing S D, Berliner J A, Valente A J et al. Minimally modified low density lipoprotein induces monocyte chemotactic protein 1 in human endothelial cells and smooth muscle cells. Proc Natl Acad Sci USA. 1990; 87 5134-5138
- 6 Liao F, Berliner J A, Mehrabian M et al. Minimally modified low density lipoprotein is biologically active in vivo in mice. J Clin Invest. 1991; 87 2253-2257
- 7 Ni W, Kitamoto S, Ishibashi M et al. Monocyte chemoattractant protein-1 is an essential inflammatory mediator in angiotensin ii-induced progression of established atherosclerosis in hypercholesterolemic mice. Arterioscler Thromb Vasc Biol. 2004; 24 534-539
- 8 Gautier E L, Jakubzick C, Randolph G J. Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. Arterioscler Thromb Vasc Biol. 2009; 29 1412-1418
- 9 Namiki M, Kawashima S, Yamashita T et al. Local overexpression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion: Synergism with hypercholesterolemia. Arterioscler Thromb Vasc Biol. 2002; 22 115-120
- 10 Boring L, Gosling J, Cleary M, Charo I F. Decreased lesion formation in ccr2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998; 394 894-897
- 11 Charo I F, Ransohoff R M. The many roles of chemokines and chemokine receptors in inflammation. N Engl J Med. 2006; 354 610-621
- 12 Gu L, Okada Y, Clinton S K et al. Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell. 1998; 2 275-281
- 13 Dawson T C, Kuziel W A, Osahar T A, Maeda N. Absence of cc chemokine receptor-2 reduces atherosclerosis in apolipoprotein e-deficient mice. Atherosclerosis. 1999; 143 205-211
- 14 Gosling J, Slaymaker S, Gu L et al. Mcp-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein b. J Clin Invest. 1999; 103 773-778
- 15 Guo J, Van Eck M, Twisk J et al. Transplantation of monocyte cc-chemokine receptor 2-deficient bone marrow into apoe3-leiden mice inhibits atherogenesis. Arterioscler Thromb Vasc Biol. 2003; 23 447-453
- 16 Guo J, de Waard V, Van Eck M et al. Repopulation of apolipoprotein e knockout mice with ccr2-deficient bone marrow progenitor cells does not inhibit ongoing atherosclerotic lesion development. Arterioscler Thromb Vasc Biol. 2005; 25 1014-1019
- 17 Ni W, Egashira K, Kitamoto S et al. New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein e-knockout mice. Circulation. 2001; 103 2096-2101
- 18 Inoue S, Egashira K, Ni W et al. Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein e-knockout mice. Circulation. 2002; 106 2700-2706
- 19 Tsou C-L, Peters W, Si Y et al. Critical roles for ccr2 and mcp-3 in monocyte mobilization from bone marrow and recruitment to inflammatory sites. J Clin Invest. 2007; 117 902-909
- 20 Aiello R J, Perry B D, Bourassa P A et al. Ccr2 receptor blockade alters blood monocyte subpopulations but does not affect atherosclerotic lesions in apoe(-/-) mice. Atherosclerosis. 2010; 208 370-375
- 21 Jones K L, Maguire J J, Davenport A P. Chemokine receptor ccr5: From aids to atherosclerosis. Br J Pharmacol. 2011; 162 1453-1469
- 22 Weber C, Belge K U, von Hundelshausen P et al. Differential chemokine receptor expression and function in human monocyte subpopulations. J Leukoc Biol. 2000; 67 699-704
- 23 Tacke F, Alvarez D, Kaplan T J et al. Monocyte subsets differentially employ ccr2, ccr5, and cx3cr1 to accumulate within atherosclerotic plaques. J Clin Invest. 2007; 117 185-194
- 24 Kuziel W A, Dawson T C, Quinones M et al. Ccr5 deficiency is not protective in the early stages of atherogenesis in apoe knockout mice. Atherosclerosis. 2003; 167 25-32
- 25 Braunersreuther V, Zernecke A, Arnaud C et al. Ccr5 but not ccr1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol. 2007; 27 373-379
- 26 Quinones M P, Martinez H G, Jimenez F et al. Cc chemokine receptor 5 influences late-stage atherosclerosis. Atherosclerosis. 2007; 195 92-103
- 27 Potteaux S, Combadiere C, Esposito B et al. Role of bone marrow-derived cc-chemokine receptor 5 in the development of atherosclerosis of low-density lipoprotein receptor knockout mice. Arterioscler Thromb Vasc Biol. 2006; 26 1858-1863
- 28 Hyde C L, MacInnes A, Sanders F A et al. Genetic association of the ccr5 region with lipid levels in at-risk cardiovascular patients/clinical perspective. Circ Cardiovasc Genet. 2010; 3 162-168
- 29 Afzal A R, Kiechl S, Daryani Y P et al. Common ccr5-del32 frameshift mutation associated with serum levels of inflammatory markers and cardiovascular disease risk in the bruneck population. Stroke. 2008; 39 1972-1978
- 30 Szalai C, Duba J, Prohaszka Z et al. Involvement of polymorphisms in the chemokine system in the susceptibility for coronary artery disease (cad). Coincidence of elevated lp(a) and mcp-1 – 2518 g/g genotype in cad patients. Atherosclerosis. 2001; 158 233-239
- 31 Simeoni E, Winkelmann B R, Hoffmann M M et al. Association of rantes g-403a gene polymorphism with increased risk of coronary arteriosclerosis. Eur Heart J. 2004; 25 1438-1446
- 32 Koenen R R, von Hundelshausen P, Nesmelova I V et al. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med. 2009; 15 97-103
- 33 Schober A, Manka D, von Hundelshausen P et al. Deposition of platelet rantes triggering monocyte recruitment requires p-selectin and is involved in neointima formation after arterial injury. Circulation. 2002; 106 1523-1529
- 34 von Hundelshausen P, Weber K S, Huo Y et al. Rantes deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation. 2001; 103 1772-1777
- 35 Huo Y, Schober A, Forlow S B et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein e. Nat Med. 2003; 9 61-67
- 36 Veillard N R, Kwak B, Pelli G et al. Antagonism of rantes receptors reduces atherosclerotic plaque formation in mice. Circ Res. 2004; 94 253-261
- 37 Braunersreuther V, Steffens S, Arnaud C et al. A novel rantes antagonist prevents progression of established atherosclerotic lesions in mice. Arterioscler Thromb Vasc Biol. 2008; 28 1090-1096
- 38 Haley K J, Lilly C M, Yang J-H et al. Overexpression of eotaxin and the ccr3 receptor in human atherosclerosis: Using genomic technology to identify a potential novel pathway of vascular inflammation. Circulation. 2000; 102 2185-2189
- 39 Lutgens E, Faber B, Schapira K et al. Gene profiling in atherosclerosis reveals a key role for small inducible cytokines: Validation using a novel monocyte chemoattractant protein monoclonal antibody. Circulation. 2005; 111 3443-3452
- 40 Wilcox J N, Nelken N A, Coughlin S R et al. Local expression of inflammatory cytokines in human atherosclerotic plaques. J Atheroscler Thromb. 1994; (Suppl 1) 10-13
- 41 Umehara H, Bloom E T, Okazaki T et al. Fractalkine in vascular biology: From basic research to clinical disease. Arterioscler Thromb Vasc Biol. 2004; 24 34-40
- 42 Ancuta P, Rao R, Moses A et al. Fractalkine preferentially mediates arrest and migration of cd16+ monocytes. J Exp Med. 2003; 197 1701-1707
- 43 McDermott D H, Fong A M, Yang Q et al. Chemokine receptor mutant cx3cr1-m280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. J Clin Invest. 2003; 111 1241-1250
- 44 Schulz C, Schafer A, Stolla M et al. Chemokine fractalkine mediates leukocyte recruitment to inflammatory endothelial cells in flowing whole blood: A critical role for p-selectin expressed on activated platelets. Circulation. 2007; 116 764-773
- 45 Combadiere C, Potteaux S, Gao J L et al. Decreased atherosclerotic lesion formation in cx3cr1/apolipoprotein e double knockout mice. Circulation. 2003; 107 1009-1016
- 46 Lesnik P, Haskell C A, Charo I F. Decreased atherosclerosis in cx3cr1-/- mice reveals a role for fractalkine in atherogenesis. J Clin Invest. 2003; 111 333-340
- 47 Teupser D, Pavlides S, Tan M et al. Major reduction of atherosclerosis in fractalkine (cx3cl1)-deficient mice is at the brachiocephalic artery, not the aortic root. Proc Natl Acad Sci USA. 2004; 101 17.795-17.800
- 48 Saederup N, Chan L, Lira S A, Charo I F. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion formation in ccr2-/- mice: Evidence for independent chemokine functions in atherogenesis. Circulation. 2008; 117 1642-1648
- 49 Liu P, Yu Y-R A, Spencer J A et al. Cx3cr1 deficiency impairs dendritic cell accumulation in arterial intima and reduces atherosclerotic burden. Arterioscler Thromb Vasc Biol. 2008; 28 243-250
- 50 Landsman L, Bar-On L, Zernecke A et al. Cx3cr1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. Blood. 2008; 113 963-972
- 51 Cheng C, Tempel D, van Haperen R et al. Shear stress-induced changes in atherosclerotic plaque composition are modulated by chemokines. J Clin Invest. 2007; 117 616-626
- 52 Boisvert W A, Santiago R, Curtiss L K, Terkeltaub R A. A leukocyte homologue of the il-8 receptor cxcr-2 mediates the accumulation of macrophages in atherosclerotic lesions of ldl receptor-deficient mice. J Clin Invest. 1998; 101 353-363
- 53 Huo Y, Weber C, Forlow S B et al. The chemokine kc, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium. J Clin Invest. 2001; 108 1307-1314
- 54 Zhou Z, Subramanian P, Sevilmis G et al. Lipoprotein-derived lysophosphatidic acid promotes atherosclerosis by releasing cxcl1 from the endothelium. Cell Metab. 2011; 13 592-600
- 55 Schwartz D, Andalibi A, Chaverri-Almada L et al. Role of the GRO family of chemokines in monocyte adhesion to MM-LDL-stimulated endothelium. J Clin Invest. 1994; 94 1968-1973
- 56 Boisvert W A, Rose D M, Johnson K A et al. Up-regulated expression of the cxcr2 ligand kc/gro-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol. 2006; 168 1385-1395
- 57 Bernhagen J, Krohn R, Lue H et al. Mif is a noncognate ligand of cxc chemokine receptors in inflammatory and atherogenic cell recruitment. Nat Med. 2007; 13 587-596
- 58 Schober A, Bernhagen J, Thiele M et al. Stabilization of atherosclerotic plaques by blockade of macrophage migration inhibitory factor after vascular injury in apolipoprotein e-deficient mice. Circulation. 2004; 109 380-385
- 59 Viola A, Luster A D. Chemokines and their receptors: Drug targets in immunity and inflammation. Annu Rev Pharmacol Toxicol. 2008; 48 171-197
- 60 Abi-Younes S, Sauty A, Mach F et al. The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res. 2000; 86 131-138
- 61 Damas J K, Waehre T, Yndestad A et al. Stromal cell-derived factor-1alpha in unstable angina: Potential antiinflammatory and matrix-stabilizing effects. Circulation. 2002; 106 36-42
- 62 Zernecke A, Bot I, Djalali-Talab Y et al. Protective role of cxc receptor 4/cxc ligand 12 unveils the importance of neutrophils in atherosclerosis. Circ Res. 2008; 102 209-217
- 63 Zernecke A, Bidzhekov K, Noels H et al. Delivery of microrna-126 by apoptotic bodies induces cxcl12-dependent vascular protection. Sci Signal. 2009; 2 ra81
- 64 Samani N J, Erdmann J, Hall A S et al. Genomewide association analysis of coronary artery disease. N Engl J Med. 2007; 357 443-453
- 65 Kathiresan S, Voight B F, Purcell S et al. Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants. Nat Genet. 2009; 41 334-341
- 66 Mehta N N, Li M, William D et al. The novel atherosclerosis locus at 10q11 regulates plasma cxcl12 levels. Eur Heart J. 2011; 32 963-971
- 67 Kiechl S, Laxton R C, Xiao Q et al. Coronary artery disease-related genetic variant on chromosome 10q11 is associated with carotid intima-media thickness and atherosclerosis. Arterioscler Thromb Vasc Biol. 2010; 30 2678-2683
- 68 Schall T J, Proudfoot A E. Overcoming hurdles in developing successful drugs targeting chemokine receptors. Nat Rev Immunol. 2011; 11 355-363
- 69 Gilbert J, Lekstrom-Himes J, Donaldson D et al. Effect of cc chemokine receptor 2 ccr2 blockade on serum c-reactive protein in individuals at atherosclerotic risk and with a single nucleotide polymorphism of the monocyte chemoattractant protein-1 promoter region. Am J Cardiol. 2011; 107 906-911
Univ.-Prof. Dr. med. Andreas Schober
Institut für Molekulare
Herz-Kreislaufforschung
Medizinische Fakultät der RWTH
Aachen
Pauwelsstr. 30
52074 Aachen
eMail: aschober@ukaachen.de