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)

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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 21
Jones K L, Maguire J J, Davenport A P.
Chemokine receptor ccr5: From aids to atherosclerosis.
Br J Pharmacol.
2011;
162
1453-1469
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 26
Quinones M P, Martinez H G, Jimenez F et al.
Cc chemokine receptor 5 influences late-stage
atherosclerosis.
Atherosclerosis.
2007;
195
92-103
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 59
Viola A, Luster A D.
Chemokines and their receptors: Drug targets in immunity and
inflammation.
Annu Rev Pharmacol Toxicol.
2008;
48
171-197
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 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
MissingFormLabel
- 68
Schall T J, Proudfoot A E.
Overcoming hurdles in developing successful drugs targeting
chemokine receptors.
Nat Rev Immunol.
2011;
11
355-363
MissingFormLabel
- 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
MissingFormLabel
Univ.-Prof. Dr. med. Andreas Schober
Institut für Molekulare
Herz-Kreislaufforschung
Medizinische Fakultät der RWTH
Aachen
Pauwelsstr. 30
52074 Aachen
eMail: aschober@ukaachen.de