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Originally published online as doi:10.1189/jlb.1206761 on March 29, 2007

Published online before print March 29, 2007
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(Journal of Leukocyte Biology. 2007;82:226-236.)
© 2007 by Society for Leukocyte Biology

Chemokine regulation of atherosclerosis

Jana Barlic and Philip M. Murphy1

Molecular Signaling Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA

1 Correspondence: NIH, NIAID, Bldg. 10, Rm. 11N113, Bethesda, MD 20892, USA. E-mail: pmm{at}nih.gov

ABSTRACT

Oxidative stress and inflammation are accepted as major factors in the pathogenesis of atherosclerosis, but how they interact to produce a plaque has not been delineated clearly. Recent data suggest that oxidized lipids may act in part by regulating production of chemokines and chemokine receptors, which in turn, may direct monocytes and other blood leukocytes to the vessel wall, where they may interact with endothelial cells and smooth muscle cells. The receptors may act at the level of recruitment, retention, and egress, not only through classic, chemotactic mechanisms but also through direct, intercellular adhesion. The results suggest a coordinated mechanism for inflammatory cell accumulation in plaque and identify novel targets, such as CCR2 and CX3CR1, for potential drug development in coronary artery disease.

Key Words: leukocytes • atherogenesis

INTRODUCTION

Risk of coronary artery disease is determined by a complex combination of genetic and environmental factors. Against this background, atherogenic triggers are thought to include injury to vascular endothelium and local accumulation of oxidized low-density lipoprotein (oxLDL) in the large arteries. Each of the lipid constituents of LDL, including cholesteryl esters, phospholipids, sterols, and triglycerides, can undergo oxidation, and it is thought that oxLDL and/or its free lipid constituents induce factors that promote infiltration of vascular subendothelium by monocytes. There, the cells mature into lipid-laden, foamy macrophages. The foam cell is the principal leukocyte present in fatty streaks, the earliest pathologic sign of atherosclerosis. Invading monocytes release proinflammatory cytokines, chemoattractants, and enzymes, which degrade extracellular matrix components, thus allowing T lymphocytes, NK cells, dendritic cells (DC), mast cells, and smooth muscle cells (SMCs) to invade the vascular subendothelium. Inflammatory cytokines also activate resident cells in the lesion, which may contribute to plaque erosion and rupture, forming a surface on which activated platelets may initiate thrombosis and amplify inflammation, leading to the acute coronary syndrome [1 ].

Recent work has implicated specific cytokines, TLRs, adhesion molecules, and chemokines in atherogenesis. In some cases, evidence for plausible roles in pathogenesis has been obtained through associations of functional genetic polymorphisms in patients (Tables 1 and 2 ). Here, we focus our attention on the chemokines.


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  		Table 1. Genetic Evidence Supporting Direct Roles of Chemokines and Chemokine Receptors in Atherogenesis in Mouse and Man


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  		Table 2. Genetic Evidence Supporting Direct Roles of Cytokines, Adhesion Molecules, Toll-like Receptors and Matrix Metalloproteinases in Atherogenesis in Mouse and Man

Chemokines are divided into four major subfamilies: C, CC, CXC, CX3C, based on the number and positioning of conserved cysteines in the aminoterminal region of the molecule. They are predominantly secreted, heparin-binding proteins, which regulate leukocyte trafficking to and activation at sites of infection or inflammation through interactions with their cognate seven-transmembrane domain G protein-coupled receptors. There are ~42 human chemokines and at least 18 human chemokine receptors [61 ]. In the context of atherosclerosis, it is currently thought that chemokines and chemokine receptors may coordinate communication between inflammatory cellular components of the peripheral blood and cellular components of the arterial wall, thereby regulating leukocyte influx, capture, efflux, activation, and gene regulation as well as proliferation and/or apoptosis of resident cells in the plaque (Fig. 1 ).


Figure 1
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  		Figure 1. Model for chemokine regulation of monocyte accumulation in atherosclerosis. LDL diffuses from the blood into the inner-most layer of the artery, where it undergoes oxidative modifications, forming randomly distributed, extracellular pools of oxLDL and its stable metabolites. Biologically active lipid deposits in the intima stimulate vascular endothelium to express and release adhesion molecules, proinflammatory cytokines, and chemoattractants. Circulating blood monocytes are captured by the endothelium and invade inflamed arteries through a multistep process, which includes selectin-mediated rolling, integrin-mediated firm arrest, spreading, and diapedesis. This classical model of leukocyte recruitment is in atherogenesis, supported by CXCR2-dependent capture of monocytes by activated endothelium and CCR2-dependent transendothelial migration. After entering the subendothelial space, monocytes differentiate into macrophages, and ingestion of lipids leads to foam cell formation. Foam cells are the predominant cell population in early lesions; however, macrophages and foam cells continue to secrete bioactive molecules such as growth factors and chemokines, which can recruit SMCs expressing CXCR4, CCR5, CX3CR1, or CCR2, and inflammatory cells including platelets, T cells, NK cells, NKT cells, B cells, and DC to the progressing plaques. Components of the oxLDL-rich environment silence macrophage CCR2 expression and up-regulate the adhesion chemokine receptor CX3CR1 and its ligand CX3CL1, promoting macrophage capture and retention in the plaque. Furthermore, numerous heterotypic and homotypic interactions, which are maintained by proadhesive CX3CL1-CX3CR1 contacts, may support organization of cells in the plaque. CCR7 may facilitate atheroregression. Rapid depletion of foam cells in the regression environment correlates with a substantial number of CCR7+CD68+ cells emigrating from the plaque to the local lymph nodes. Other chemoattractant receptors have been implicated in atherosclerosis (leukotriene B4 receptor, CCR5, CXCR4, CXCR3); however, their mechanisms of action have not been studied. Mo, Monocyte; M{phi}, macrophage.

CCL2 AND CCR2 IN MONOCYTE RECRUITMENT TO PLAQUE

The first chemokine implicated in atherogenesis was CCL2 (also known as MCP-1). CCL2 is not normally found in the vessel wall but is induced in the context of atherosclerosis [62 63 64 65 ]. CCL2 has been detected in macrophage-rich areas bordering the lipid core, as well as endothelial and SMCs in human, mouse, and rabbit atherosclerotic lesions [66 67 68 ]. CCL2 levels are also elevated in the systemic circulation of patients with acute coronary syndrome [69 ]. Moreover, there is genetic evidence in mouse and man to support a functional role for CCL2 in atherogenesis. In man, the SNP –2518G (alternatively –2578G) in the regulatory region of CCL2, which causes increased promoter activity, is associated with elevated, circulating levels of CCL2 [4 ] and increased risk of myocardial infarction [4 , 5 ]. In mouse, direct evidence supporting a role for CCL2 in atherogenesis has been obtained through targeted disruption of ccl2 in atherosclerosis-prone mouse strains (ldlr–/– or transgenic apoB), which resulted in a >60% decrease in lesion size and plaque macrophage content [2 , 3 ]. Conversely, overexpression of CCL2 accelerated atherosclerosis in irradiated hypercholesterolemic apoE–/– recipients [70 ].

Consistent with this, homozygous deletion of the mouse CCL2 receptor gene ccr2 abolishes CCL2-induced monocyte chemotaxis in vitro and reduced monocyte extravasation across and adhesion to vascular endothelium, which suggest a nonredundant role of CCR2 in monocyte recruitment during inflammation [71 ]. Furthermore, lack of CCR2 expression in the ccr2–/– apoE–/– mouse strain resulted in decreased susceptibility to atherosclerosis [11 ]. The importance of monocyte CCR2 in atherogenesis is supported further by studies in which transplantation of ccr2–/– bone marrow into irradiated atherosclerosis-prone apoE3-Leiden recipients strongly decreased the size of aortic root lesions [72 ]. The beneficial effect of genetic disruption of CCR2 in atherosclerosis was confirmed later at the pharmacological level using a dominant-negative, N-terminally truncated mutant of CCL2, designated 7ND, in apoE–/– mice. 7ND decreased lesion formation, macrophage accumulation, and proatherogenic cytokine production in this model [73 74 75 ].

Together, these results provide proof of principle that CCL2 induces monocyte recruitment into lesions in a CCR2-dependent manner in the mouse. In humans, CCR2 has been identified directly on foam cells [76 ]. Moreover, the CCR2-V64I SNP has been associated with increased risk of myocardial infarction and left ventricular heart failure. The significance of this result requires sharpening, as this polymorphism, which affects the coding region of CCR2, has been reported to alter receptor function in some [12 , 13 ] but not all [14] studies. Additional studies will be needed to further assess potential changes in CCR2 function as a result of this SNP and to evaluate whether it is inherited in linkage disequilibrium with other "functional" polymorphisms that may affect risk of atherosclerosis.

The favored mechanistic model of atherogenesis combines the response-to-injury and oxidative stress theories. Although the response-to-injury theory suggests that vascular injury-related events induce leukocyte infiltration into inflamed arteries [77 , 78 ], the oxidative stress theory supports the notion that modified LDL in the vessel wall may be important for initiating leukocyte recruitment [79 ]. In this regard, monocyte CCR2 expression is elevated in hypercholesterolemic patients, and normal human monocytes treated with LDL in vitro have increased expression of CCR2 and increased chemotactic responses to CCL2 [80 , 81 ]. In contrast, stimulation of human monocytes with oxLDL or end-point oxidation derivatives of linoleic acid found in human atherosclerotic lesions [9-hydroxy-10E,12Z-octadecadienoic acid ester (9-HODE) and 13-hydroxy-9Z,11E-octadecadienoic acid ester (13-HODE)] down-regulated CCR2 expression through a peroxisome-proliferator-activated receptor {gamma} (PPAR{gamma})-dependent pathway [82 ] (Fig. 2 ), a mechanism that may be considered to abort CCR2-dependent chemotaxis, promoting retention of monocytes within the lesion (Fig. 1 ). This observation establishes a functional, proatherogenic link between oxLDL and CCR2.


Figure 2
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  		Figure 2. oxLDL and its oxidized linoleic acid-containing lipids induce a chemokine receptor switch: CCR2 off, CX3CR1 on. The atheromatous microenvironment, containing a mixture of oxLDL and its end-point oxidation products (9-HODE, 13-HODE), promotes PPAR{gamma}-dependent silencing of CCR2 and increased expression of CX3CR1 on monocytes infiltrating the vascular subendothelium. This proadhesive chemokine receptor switch may prevent CCR2-dependent migration and may induce CX3CR1-dependent retention mechanisms, which together, may promote macrophage accumulation in the vessel wall.

CX3CR1 AND CXCR2 AND FOAM CELL RETENTION IN PLAQUE

Two additional chemokine receptors, CXCR2 and CX3CR1, have been implicated in monocyte/macrophage accumulation in the atherosclerotic plaque but through distinct mechanisms. The CX3CR1 ligand, CX3CL1, is an atypical, multimodular chemokine, which exists in membrane-tethered and shed forms. The immobilized form consists of a chemokine domain anchored to the plasma membrane through an extended, mucin-like stalk, a transmembrane helix, and an intracellular domain [83 ]. Full-length transmembrane CX3CL1 functions as an intercellular adhesion molecule, which mediates integrin-independent cell capture by binding to CX3CR1 on target cells [84 ]. Following disintegrin-like metalloproteinase-mediated release of the chemokine domain [85 , 86 ], CX3CL1 may also promote recruitment of CX3CR1+ monocytes, platelets, NK cells, NK-T cells, T cells, and DC to sites of inflammation [84 ]. In the CNS, CX3CL1 is constitutively expressed on neurons and CX3CR1 on microglial cells. In mouse and man, CX3CL1 is the only known ligand for CX3CR1 [61 ].

Neither CX3CL1 nor CX3CR1 has been found in normal mouse or human arterial wall; however, in the context of atherosclerosis, both molecules are expressed on foam cells and coronary artery SMCs in both species [20 , 87 ]. Targeted disruption of cx3cl1 or cx3cr1 does not affect viability or fertility or lead to spontaneous infections in mice. However, deletion of cx3cr1 in apoE–/– mice or cx3cl1 in ldlr–/– or apoE–/– mice decreases susceptibility to atherosclerosis. Although two independently derived lines of cx3cr1–/–apoE–/– mice showed decreased lesion formation, and fewer macrophages infiltrated plaque in the aortic root, the cx3cl1–/–apoE–/– strain had decreased atherosclerosis in the brachiocephalic artery, and cx3cl1–/–ldlr–/– mice displayed smaller lesions in the aortic root and the brachiocephalic artery [10 , 20 , 21 ]. These data suggest that in the mouse, CX3CL1 interaction with CX3CR1 promotes atherogenesis.

Consistent with this, analysis of human CX3CR1 has identified two SNPs common in all racial groups in the coding region, I249V and T280M, which have been associated with decreased risk of atherosclerosis. In retrospective cohort studies, these polymorphisms, which are in complete linkage disequilibrium, have been associated consistently with reduced prevalence of disease endpoints, including coronary endothelial dysfunction and physical coronary artery stenosis in a National Heart, Lung and Blood Institute cardiac catheterization cohort [22 ], reduced prevalence of acute coronary events in the ACABI cohort [23 ], and reduced progression of carotid atherosclerosis [24 ]. Association with lower risk of cardiovascular events was also observed in the population-based prospective, Framingham Heart Study Offspring Cohort [25 ]. The variant receptor will be referred to here as CX3CR1-M280. Further investigations exploring putative mechanisms of action demonstrated that CX3CR1-M280 mediated decreased CX3CL1-induced chemotaxis of primary NK cells from homozygotes. In studies of the variant receptor expressed in transfected cells, defects were observed in the on rate for binding the iodinated chemokine domain of CX3CL1 and in immobilized CX3CL1-dependent adhesion under conditions of physiologic shear [25 ]. It is important to note that in an independent study, Daoudi et al. [88 ] were unable to confirm this and in contrast, showed that CX3CR1-M280, tested in transfected cells and at natural abundance in primary cells from homozygotes, promotes substantially greater intercellular CX3CL1-dependent adhesion than wild-type CX3CR1. Subsequently, the claim of an impaired adhesion phenotype for CX3CR1-M280 was reproduced independently by David McDermott (Laboratory of Molecular Immunology, NIAID, NIH), working in the authors’ laboratory (unpublished data). Further work will be needed to clarify this discrepancy; however, regardless of whether CX3CR1-M280 functions as a gain- or loss-of-function mutant, it has been reported consistently to function abnormally and to be associated consistently with reduced risk of cardiovascular disease in man with odds ratios ranging from 0.56 to 0.7. This is consistent with loss-of-function protection from atherosclerosis in multiple independent models using two different strains of knockout mice targeting the receptor and one targeting the ligand.

Recently, biochemical and functional experiments have suggested that modulation of expression of CX3CL1 and CX3CR1 in the context of atherosclerosis may be important [89 ]. In contrast to CCR2, oxLDL and its oxidized linoleic acid metabolites are able to specifically induce differentiation of human CX3CR1low monocytes to CX3CR1high macrophages, which adhere strongly to CX3CL1+ primary human coronary artery SMCs under static conditions. Blocking experiments indicated that adhesion was mediated directly and predominantly by CX3CR1. Effects of oxLDL and its end-point oxidation products on CX3CR1 expression were mediated by PPAR{gamma}, as targeting the PPAR{gamma} gene with small interfering RNA reduced receptor expression and macrophage adhesion to coronary artery SMCs [89 ].

The data suggest that in atherogenesis, oxidized lipid-driven activation of macrophage PPAR{gamma} in the intima results in a proadhesive chemokine receptor switch—CCR2 off, CX3CR1 on—causing cessation of CCR2-dependent migration and activation of CX3CR1-dependent retention mechanisms, which together, promote macrophage accumulation in the vessel wall (Fig. 1 ). The presence of distinct cell types in atherosclerotic lesions, which express the ligand and the receptor, indicates that homotypic and heterotypic cell–cell interactions are possible. In this regard, chemokine–chemokine receptor interactions not only may promote leukocyte infiltration into lesions but may also be important for anchorage, retention, and interaction with other cell types in plaque, which could be important for modulation of function. These results are in agreement with the oxidative and inflammatory hypotheses of atherosclerosis, as they pinpoint oxLDL and its derivatives as major inducers of inflammatory stimuli. More broadly, the data identify macrophage binding to coronary artery SMCs as a primary cell setting, in which CX3CR1 functions as the major adhesion system.

Nevertheless, there is evidence that CXCL8 and its receptor CXCR2 [90 , 91 ] may also promote atherosclerosis through effects on cell–cell adhesion. CXCL8 and CXCR2 have been detected in macrophage-rich, atherosclerotic plaque [92 , 93 ]. Best known as a major neutrophil chemoattractant, CXCL8 has also been reported to function as a monocyte and T cell agonist under certain conditions. A CXCL8 homologue does not exist in the mouse, but its functions are replaced by other mouse chemokines, including MIP-2 and keratinocyte-derived chemokine (KC) [94]. Irradiated ldlr–/– mice, fed an atherogenic diet after receiving bone marrow from cxcr2–/– animals, develop smaller lesions, containing fewer macrophages and SMCs than lesions of ldlr–/– recipients, which were repopulated with cxcr2+/+ bone marrow [18 ], indicating that mouse CXCR2 is an atherogenic chemokine receptor. How CXCR2 and its ligands promote atherogenesis is unclear; however, evidence shows that in atherosclerotic carotid arteries isolated from apoE–/– mice, CXCL8 mouse homologues triggered VLA-4-dependent monocyte arrest to endothelium under flow conditions [95 ]. Moreover, stimulation of human monocytes with oxLDL increased CXCR2-dependent adhesion of cells to the endothelial cell line ECV304 [96 ]. Thus, in addition to recruitment, CXCL8 and CXCR2 may promote atherogenesis by mediating adhesion of infiltrating monocytes to inflamed vascular endothelium. This notion has not yet been translated clearly to humans. There is evidence that serum levels of CXCL8 are elevated in patients with myocardial infarction [97 ], and CXCL8 and CXCR2 are strongly up-regulated following exposure of monocytes to oxLDL [96 , 98 ]. However, genetic studies in man using CXCL8 SNPs (–A353G, +T1530C, +A3331G) and CXCR2 SNPs (+C785T and +T1208C), which are suggested to increase release of CXCL8 and expression of CXCR2 [99 ], have not been associated with cardiovascular disease.

CHEMOKINES AND MECHANISMS OF ATHEROREGRESSION

Although atherosclerosis has been perceived to be a relentlessly progressive disease, studies in humans have demonstrated that at least partial regression can be achieved, e.g., in the case of simvastatin therapy and carotid plaque [100 , 101 ] and infusions of apoA–IMilano and coronary atherosclerosis [102 , 103 ]. Furthermore, transplantation of a segment of atherosclerotic aorta from hyperlipidemic apoE–/– mice to normolipidemic wild-type recipients resulted in marked plaque regression [104 , 105 ]; regression mechanisms have not been defined in these settings but may include egress of foam cells from plaques to local lymph nodes [106 ]. In this regard, it has been shown recently that emigration of CD68+ inflammatory cells from the atherosclerotic plaque is abrogated in vivo by treatment of mice with antibodies to the CCR7 ligands CCL19 and CCL21. These data suggest that egress of cells and regression mechanisms may be CCR7-dependent (Fig. 1 ) [107 ]. Given the important role of macrophages in atherogenesis, finding ways to promote their exit is of great therapeutic interest.

CHEMOKINES AND ATHEROPROTECTION

CXCL16 is the second of two atypical, multimodular chemokines, which are known, having a structure similar to CX3CL1 [108 ]. Like CX3CL1, CXCL16 may function as a membrane-tethered adhesion molecule [109 ]. It can also be shed from the plasma membrane by cleavage of the stalk, which is mediated by ADAM 10 [110 ], and thereby functions as a chemoattractant, promoting migration of T cells, NK cells, and NK-T cells to sites of infection and inflammation by triggering its private receptor CXCR6 [108 ]. CXCL16 also functions as a scavenger receptor, specifically for phosphatidylserine and oxLDL [111 ], and was originally named scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) [112 ]. Enhanced expression of membrane-bound CXCL16 has been found in human and mouse atherosclerotic plaque, colocalizing with lipid-laden, intimal macrophages and lesional SMCs, suggesting a role in the pathogenesis of cardiovascular disease [112 113 114 ]. CXCR6 has also been detected in human and mouse atherosclerotic plaques on foam cells, T cells, and SMCs [114 ].

A human epidemiologic study found that a polymorphic variant of CXCL16, CXCL16-A181V, is associated with increased coronary artery stenosis in postinfarction patients [9 ]. The mutated amino acid is located in the mucin-like, extracellular stalk of CXCL16. This is only a single study, with an odds ratio of 1.7, built on undefined plausibility, as the effect of the mutation on CXCL16 expression, shedding, and function has not been determined. In a human biomarker study, patients with stable angina pectoris, unstable angina pectoris, and myocardial infarction were surprisingly shown to have significantly lower systemic CXCL16 levels compared with healthy controls, which counterintuitively suggests that soluble CXCL16 may be atheroprotective [115 ]. It is important to note, however, that the sample size in this study was small, and potential mechanisms of action have not been defined [116]. Nevertheless, strong evidence consistent with this has been obtained in the mouse, in which cxcl16 disruption on a ldlr–/– genetic background resulted in accelerated atherosclerosis as a result of enhanced macrophage recruitment to the aortic arch [8].

CHEMOKINE-INDUCED SMC ACTIVATION AND PROLIFERATION ACCELERATE ATHEROSCLEROSIS

Although most chemokines and chemokine receptors involved in atherogenesis are expressed predominantly on leukocyte subsets infiltrating or residing in atherosclerotic plaque, recent studies have demonstrated that chemokines and their receptors may also be present on other cell types, such as SMC [117 ], which constitute the major cellular component of the arterial wall and are located predominantly in the arterial media. In healthy arteries, SMCs function to regulate vascular tone. In response to vascular injury, however, SMCs proliferate, promoting hypertension, and migrate to form part of the intimal plaque [118 ]. Although a variety of growth factors and cytokines found in atherosclerotic lesions and in the injured arterial wall have been shown to function as agonists for SMCs, stimulating their growth, proliferation, and migration [119 ], chemokine receptors, including CCR5, CCR2, and CX3CR1, add activation of additional stimulus strength, which may promote pathological responses. CCR5 has been shown to colocalize with the SMC marker {alpha}-actin in the fibrous cap, necrotic core, and atherosclerotic media [120 ]; CCR2 has been shown to play an important role in mediating SMC proliferation and intimal hyperplasia in a nonhyperlipidemic model of acute arterial injury [121 , 122 ]; and CX3CR1, which is expressed by SMCs in human and mouse atherosclerotic plaques [20 , 21 , 123 ], has been reported to promote SMC proliferation and intimal accumulation in an endothelial denudation injury model [124 ]. Although the importance of the CCR8-CCL1 axis in atherogenesis awaits testing in animal models and epidemiologic studies, receptor and ligand are abundant in atherosclerotic plaques and are induced in the arterial media in mouse models of femoral arterial injury [125 , 126 ]. CXCL8 has also been shown to induce activation, proliferation, and chemotaxis of SMCs [127 ]. Recent evidence suggests that SMCs not only contribute to intimal hyperplasia and plaque formation but also may be capable of internalizing oxLDL, as they express membrane-tethered CXCL16 [114 , 128 ].

CHEMOKINE REGULATION OF T CELL RECRUITMENT AND FUNCTION IN ATHEROSCLEROSIS

The role of T cells and adaptive immunity in atherogenesis has been the subject of several excellent recent reviews [129, 130]. Briefly, fatty streaks in apoE–/– animals contain small numbers of {alpha}β TCR-expressing CD4+ T cells, which undergo oligoclonal expansion in response to a limited set of local antigens; the frequency of CD8+ T cells is also low. The ratio of CD4+:CD8+ T cells in advanced plaque resembles that found in peripheral blood. CD4+ T cells isolated from human plaques are mostly CD45RO-expressing memory and/or effector T cells. Many potential antigens have been investigated in the context of atherosclerosis. APCs selectively internalize oxLDL through the scavenger receptor-dependent pathway. APC-processed fragments of apoLDL, referred to as "atheroantigens," bind MHC Class II and traffic to the cell surface. T cells do not react to native LDL. However, oxidative modifications of LDL, scavenger receptor endocytosis of oxLDL, and APC-dependent presentation of atheroantigens represent a sequence of events that may break T cell tolerance. This may result in differentiation of oxLDL-reactive T cells, which localize in plaque, lymph node, and blood of patients with atherosclerosis. An additional factor stimulating T cell differentiation in plaques is continuous presence of TH1 cytokines [129 , 130 ].

Consistent with this, IFN-{gamma}-inducible chemokines CXCL9, CXCL10, and CXCL11 [131 ] have been detected in endothelial cells, SMCs, and macrophages in atheromas, and the receptor for these chemokines, CXCR3, has been observed on lesional T cells [132 ]. CXCL10 deficiency in apoE–/– animals results in decreased accumulation of CD4+ T cells in lesions, and the number and activity of regulatory T cells (Tregs) increase, suggesting that CXCL10 likely stimulates atherogenesis by regulating the local balance of effectors and Tregs [7 ]. CXCR3 may have a pathogenic role in early stages of atherosclerosis, as cxcr3–/–apoE–/– animals compared with apoE–/– mice show decreased size of early but not advanced plaques. The nonredundant role of CXCR3 was also shown in the ccr2–/–cxcr3–/–apoE–/– model, in which lesion formation, inflammatory cell infiltration, and proinflammatory chemokine production were all decreased in triple knockout as compared with apoE–/– mice or deletion of either receptor in apoE–/– mice [19 ].

The precise role of CXCR3 and its chemokine ligands in atherogenesis in man remains uncertain. CXCL9, CXCL10, and CXCL11 as well as CXCR3 are all polymorphic; however, the functional effect of polymorphism and associations of polymorphism with cardiovascular disease have not yet been delineated [133 134 135 ].

CCL5 AND CCL5 RECEPTORS IN ATHEROGENESIS

A role in atherogenesis for CCL5 must also be considered, as it is expressed in large amounts by foam cells and activated T cells in mouse and human atheromas [136 137 138 ]. Two gain-of-function polymorphisms in the human CCL5 promoter (C28G, G403A) have been identified [139 , 140 ], one of which, CCL5-G403A, has been associated with increased risk of coronary artery disease in a single study [6 ]. Consistent with this, administration of Met-CCL5, which acts as a potent antagonist of the CCL5 receptors CCR5 and CCR1, but not CCR3, into ldlr–/– animals, inhibited atherosclerosis partially by decreasing plaque formation and infiltration of macrophages and T cells into lesions [136 ]. Moreover, the major HIV/AIDS restriction mutation CCR5{Delta}32, which causes truncation and loss-of-function of CCR5, has been associated with decreased risk of myocardial infarction in some [17 ] but not all cohorts studied to date [22 , 141 ]. The initial study determining the role of CCR5 in atherogenesis showed that CCR5 deficiency in apoE–/– mice was not found to alter susceptibility to atherosclerosis after 16 weeks [15 ]. However, in a follow-up study, in which progression of atherosclerosis in ccr5–/–apoE–/– was monitored for 10 and 12 weeks, lack of CCR5 expression decreased lesion formation by ~50%. Furthermore, animals followed longer, out to 22 weeks on a high-fat diet or to 26 weeks on a chow diet, were reported to be protected against lesion formation [16 ], suggesting that CCR5 may promote progression of atherosclerosis. Taken together, the human and mouse data provide suggestive evidence for a role for CCL5 and CCL5 receptors in atherogenesis, but additional work will be needed to explain at a mechanistic level the discrepant results from different cohorts and different mouse protocols.

CONCLUSIONS

Atherosclerosis is a multifactorial disease, in which combinatorial effects of proinflammatory cytokines, MMPs, TLRs, adhesion molecules, chemokines, and other chemoattractants may determine the outcome. Although strong data implicating specific chemokines and chemokine receptors in atherogenesis are now emerging, there are still major gaps in knowledge before this can be translated to the clinic. First, most of the research has been focused on the role of chemokines and chemokine receptors in early stages of atherosclerosis. Roles of the chemokine system in progression and regression of disease remain unknown. Second, the lack of good, surrogate markers makes measurement of efficacy for any potential treatment targeting chemokine action at the vessel wall difficult. Third, interaction of the atheromatous environment and cardiovascular drugs with chemokines and chemokine receptors is poorly understood. Further research in these areas may provide new opportunities to understand chemokine regulation of atherogenesis and to apply this knowledge to the treatment of atherosclerotic cardiovascular disease.

Received December 24, 2006; revised February 1, 2007; accepted February 6, 2007.

REFERENCES

    1
  1. Ross, R. (1999) Atherosclerosis—an inflammatory disease N. Engl. J. Med. 340,115-126[Free Full Text]
    2. 2
  2. Gosling, J., Slaymaker, S., Gu, L., Tseng, S., Zlot, C. H., Young, S. G., Rollins, B. J., Charo, I. F. (1999) MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B J. Clin. Invest. 103,773-778[Medline]
    3. 3
  3. Gu, L., Okada, Y., Clinton, S. K., Gerard, C., Sukhova, G. K., Libby, P., Rollins, B. J. (1998) Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice Mol. Cell 2,275-281[CrossRef][Medline]
    4. 4
  4. McDermott, D. H., Yang, Q., Kathiresan, S., Cupples, L. A., Massaro, J. M., Keaney, J. F., Jr, Larson, M. G., Vasan, R. S., Hirschhorn, J. N., O’Donnell, C. J., et al (2005) CCL2 polymorphisms are associated with serum monocyte chemoattractant protein-1 levels and myocardial infarction in the Framingham Heart Study Circulation 112,1113-1120[Abstract/Free Full Text]
    5. 5
  5. Szalai, C., Duba, J., Prohaszka, Z., Kalina, A., Szabo, T., Nagy, B., Horvath, L., Csaszar, A. (2001) 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 158,233-239[CrossRef][Medline]
    6. 6
  6. Boger, C. A., Fischereder, M., Deinzer, M., Aslanidis, C., Schmitz, G., Stubanus, M., Banas, B., Kruger, B., Riegger, G. A., Kramer, B. K. (2005) RANTES gene polymorphisms predict all-cause and cardiac mortality in type 2 diabetes mellitus hemodialysis patients Atherosclerosis 183,121-129[CrossRef][Medline]
    7. 7
  7. Heller, E. A., Liu, E., Tager, A. M., Yuan, Q., Lin, A. Y., Ahluwalia, N., Jones, K., Koehn, S. L., Lok, V. M., Aikawa, E., et al (2006) Chemokine CXCL10 promotes atherogenesis by modulating the local balance of effector and regulatory T cells Circulation 113,2301-2312[Abstract/Free Full Text]
    8. 8
  8. Aslanian, A. M., Charo, I. F. (2006) Targeted disruption of the scavenger receptor and chemokine CXCL16 accelerates atherosclerosis Circulation 114,583-590[CrossRef][Medline]
    9. 9
  9. Lundberg, G. A., Kellin, A., Samnegard, A., Lundman, P., Tornvall, P., Dimmeler, S., Zeiher, A. M., Hamsten, A., Hansson, G. K., Eriksson, P. (2005) Severity of coronary artery stenosis is associated with a polymorphism in the CXCL16/SR-PSOX gene J. Intern. Med. 257,415-422[CrossRef][Medline]
    10. 10
  10. Teupser, D., Pavlides, S., Tan, M., Gutierrez-Ramos, J. C., Kolbeck, R., Breslow, J. L. (2004) Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root Proc. Natl. Acad. Sci. USA 101,17795-17800[Abstract/Free Full Text]
    11. 11
  11. Boring, L., Gosling, J., Cleary, M., Charo, I. F. (1998) Decreased lesion formation in CCR2–/– mice reveals a role for chemokines in the initiation of atherosclerosis Nature 394,894-897[CrossRef][Medline]
    12. 12
  12. Ortlepp, J. R., Vesper, K., Mevissen, V., Schmitz, F., Janssens, U., Franke, A., Hanrath, P., Weber, C., Zerres, K., Hoffmann, R. (2003) Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age J. Mol. Med. 81,363-367[Medline]
    13. 13
  13. Petrkova, J., Cermakova, Z., Drabek, J., Lukl, J., Petrek, M. (2003) CC chemokine receptor (CCR)2 polymorphism in Czech patients with myocardial infarction Immunol. Lett. 88,53-55[CrossRef][Medline]
    14. 14
  14. Valdes, A. M., Wolfe, M. L., O’Brien, E. J., Spurr, N. K., Gefter, W., Rut, A., Groot, P. H. E., Rader, D. J. (2002) Val64Ile polymorphism in the C–C chemokine receptor 2 is associated with reduced coronary artery calcification Arterioscler. Thromb. Vasc. Biol. 22,1924-1928[Abstract/Free Full Text]
    15. 15
  15. Kuziel, W. A., Dawson, T. C., Quinones, M., Garavito, E., Chenaux, G., Ahuja, S. S., Reddick, R. L., Maeda, N. (2003) CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice Atherosclerosis 167,25-32[CrossRef][Medline]
    16. 16
  16. Braunersreuther, V., Zernecke, A., Steffens, S., Liehn, E. A., Arnaud, C., Shagdarsuren, E., Bidzhekov, K., Burger, F., Pelli, G., Luckow, B., et al (2006) Ccr5 but not Ccr1 deficiency reduces development of diet-induced atherosclerosis in mice Arterioscler. Thromb. Vasc. Biol. 27,373-379[CrossRef]
    17. 17
  17. Gonzalez, P., Alvarez, R., Batalla, A., Reguero, J. R., Alvarez, V., Astudillo, A., Cubero, G. I., Cortina, A., Coto, E. (2001) Genetic variation at the chemokine receptors CCR5/CCR2 in myocardial infarction Genes Immun. 2,191-195[CrossRef][Medline]
    18. 18
  18. Boisvert, W. A., Rose, D. M., Johnson, K. A., Fuentes, M. E., Lira, S. A., Curtiss, L. K., Terkeltaub, R. A. (2006) 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. 168,1385-1395[Abstract/Free Full Text]
    19. 19
  19. Veillard, N. R., Steffens, S., Pelli, G., Lu, B., Kwak, B. R., Gerard, C., Charo, I. F., Mach, F. (2005) Differential influence of chemokine receptors CCR2 and CXCR3 in development of atherosclerosis in vivo Circulation 112,870-878[Abstract/Free Full Text]
    20. 20
  20. Lesnik, P., Haskell, C. A., Charo, I. F. (2003) Decreased atherosclerosis in CX3CR1–/– mice reveals a role for fractalkine in atherogenesis J. Clin. Invest. 111,333-340[CrossRef][Medline]
    21. 21
  21. Combadiere, C., Potteaux, S., Gao, J. L., Esposito, B., Casanova, S., Lee, E. J., Debre, P., Tedgui, A., Murphy, P. M., Mallat, Z. (2003) Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice Circulation 107,1009-1016[Abstract/Free Full Text]
    22. 22
  22. McDermott, D. H., Halcox, J. P. J., Schenke, W. H., Waclawiw, M. A., Merrell, M. N., Epstein, N., Quyyumi, A. A., Murphy, P. M. (2001) Association between polymorphism in the chemokine receptor CX3CR1 and coronary vascular endothelial dysfunction and atherosclerosis Circ. Res. 89,401-407[Abstract/Free Full Text]
    23. 23
  23. Moatti, D., Faure, S., Fumeron, F., Amara, M. E. W., Seknadji, P., McDermott, D. H., Debre, P., Aumont, M. C., Murphy, P. M., de Prost, D., Combadiere, C. (2001) Polymorphism in the fractalkine receptor CX3CR1 as a genetic risk factor for coronary artery disease Blood 97,1925-1928[Abstract/Free Full Text]
    24. 24
  24. Ghilardi, G., Biondi, M. L., Turri, O., Guagnellini, E., Scorza, R. (2004) Internal carotid artery occlusive disease and polymorphisms of fractalkine receptor CX3CR1: a genetic risk factor Stroke 35,1276-1279[Abstract/Free Full Text]
    25. 25
  25. McDermott, D. H., Fong, A. M., Yang, Q., Sechler, J. M., Cupples, L. A., Merrell, M. N., Wilson, P. W. F., D’Agostino, R. B., O’Donnell, C. J., Patel, D. D., Murphy, P. M. (2003) Chemokine receptor mutant CX3CR1–M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans J. Clin. Invest. 111,1241-1250[CrossRef][Medline]
    26. 26
  26. Gupta, S., Pablo, A. M., Jiang, X., Wang, N., Tall, A. R., Schindler, C. (1997) IFN-{gamma} potentiates atherosclerosis in ApoE knock-out mice J. Clin. Invest. 99,2752-2761[Medline]
    27. 27
  27. Whitman, S. C., Ravisankar, P., Daugherty, A. (2002) IFN-{gamma} deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E–/– mice J. Interferon Cytokine Res. 22,661-670[CrossRef][Medline]
    28. 28
  28. Harvey, E. J., Ramji, D. P. (2005) Interferon-[{gamma}] and atherosclerosis: pro- or anti-atherogenic? Cardiovasc. Res. 67,11-20[Abstract/Free Full Text]
    29. 29
  29. Branen, L., Hovgaard, L., Nitulescu, M., Bengtsson, E., Nilsson, J., Jovinge, S. (2004) Inhibition of tumor necrosis factor-{{alpha}} reduces atherosclerosis in apolipoprotein E knockout mice Arterioscler. Thromb. Vasc. Biol. 24,2137-2142[Abstract/Free Full Text]
    30. 30
  30. Isoda, K., Sawada, S., Ishigami, N., Matsuki, T., Miyazaki, K., Kusuhara, M., Iwakura, Y., Ohsuzu, F. (2004) Lack of interleukin-1 receptor antagonist modulates plaque composition in apolipoprotein E-deficient mice Arterioscler. Thromb. Vasc. Biol. 24,1068-1073[Abstract/Free Full Text]
    31. 31
  31. Francis, S. E., Camp, N. J., Dewberry, R. M., Gunn, J., Syrris, P., Carter, N. D., Jeffery, S., Kaski, J. C., Cumberland, D. C., Duff, G. W., Crossman, D. C. (1999) Interleukin-1 receptor antagonist gene polymorphism and coronary artery disease Circulation 99,861-866[Abstract/Free Full Text]
    32. 32
  32. Davenport, P., Tipping, P. G. (2003) The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice Am. J. Pathol. 163,1117-1125[Abstract/Free Full Text]
    33. 33
  33. Elhage, R., Jawien, J., Rudling, M., Ljunggren, H. G., Takeda, K., Akira, S., Bayard, F., Hansson, G. K. (2003) Reduced atherosclerosis in interleukin-18 deficient apolipoprotein E-knockout mice Cardiovasc. Res. 59,234-240[Abstract/Free Full Text]
    34. 34
  34. Tiret, L., Godefroy, T., Lubos, E., Nicaud, V., Tregouet, D. A., Barbaux, S., Schnabel, R., Bickel, C., Espinola-Klein, C., Poirier, O., . AtheroGene Investigatorset al (2005) Genetic analysis of the interleukin-18 system highlights the role of the interleukin-18 gene in cardiovascular disease Circulation 112,643-650[Abstract/Free Full Text]
    35. 35
  35. Lutgens, E., Gijbels, M., Smook, M., Heeringa, P., Gotwals, P., Koteliansky, V. E., Daemen, M. J. A. P. (2002) Transforming growth factor-{β} mediates balance between inflammation and fibrosis during plaque progression Arterioscler. Thromb. Vasc. Biol. 22,975-982[Abstract/Free Full Text]
    36. 36
  36. Li, D., Liu, Y., Chen, J., Velchala, N., Amani, F., Nemarkommula, A., Chen, K., Rayaz, H., Zhang, D., Liu, H. (2006) Suppression of atherogenesis by delivery of using adeno-associated virus type 2 in LDLR knockout mice Biochem. Biophys. Res. Commun. 344,701-707[CrossRef][Medline]
    37. 37
  37. Eefting, D., Schepers, A., De Vries, M. R., Pires, N. M. M., Grimbergen, J. M., Lagerweij, T., Nagelkerken, L. M., Monraats, P. S., Jukema, J. W., van Bockel, J. H., Quax, P. H. A. (2006) The effect of interleukin-10 knock-out and overexpression on neointima formation in hypercholesterolemic APOE*3-Leiden mice. Atherosclerosis, Epub ahead of print.
    38. 38
  38. Binder, C. J., Hartvigsen, K., Chang, M. K., Miller, M., Broide, D., Palinski, W., Curtiss, L. K., Corr, M., Witztum, J. L. (2004) IL-5 links adaptive and natural immunity specific for epitopes of oxidized LDL and protects from atherosclerosis J. Clin. Invest. 114,427-437[CrossRef][Medline]
    39. 39
  39. Wenzel, K., Stahn, R., Speer, A., Denner, K., Glaser, C., Affeldt, M., Moobed, M., Scheer, A., Baumann, G., Felix, S. B. (1999) Functional characterization of atherosclerosis-associated Ser128Arg and Leu554Phe E-selectin mutations Biol. Chem. 380,661-667[CrossRef][Medline]
    40. 40
  40. Wenzel, K., Felix, S., Kleber, F. X., Brachold, R., Menke, T., Schattke, S., Schulte, K. L., Glaser, C., Rohde, K., Baumann, G. (1994) E-selectin polymorphism and atherosclerosis: an association study Hum. Mol. Genet. 3,1935-1937[Abstract/Free Full Text]
    41. 41
  41. Herrmann, S. M., Ricard, S., Nicaud, V., Mallet, C., Evans, A., Ruidavets, J. B., Arveiler, D., Luc, G., Cambien, F. (1998) The P-selectin gene is highly polymorphic: reduced frequency of the Pro715 allele carriers in patients with myocardial infarction Hum. Mol. Genet. 7,1277-1284[Abstract/Free Full Text]
    42. 42
  42. Jiang, H., Klein, R. M., Niederacher, D., Du, M., Marx, R., Horlitz, M., Boerrigter, G., Lapp, H., Scheffold, T., Krakau, I., Gulker, H. (2002) C/T polymorphism of the intercellular adhesion molecule-1 gene (exon 6, codon 469). A risk factor for coronary heart disease and myocardial infarction Int. J. Cardiol. 84,171-177[CrossRef][Medline]
    43. 43
  43. Sasaoka, T., Kimura, A., Hohta, S., Fukuda, N., Kurosawa, T., Izumi, T. (2001) Polymorphisms in the platelet-endothelial cell adhesion molecule-1 (PECAM-1) gene, Asn563Ser and Gly670Arg, associated with myocardial infarction in the Japanese Ann. N. Y. Acad. Sci. 947,259-270[Medline]
    44. 44
  44. Moshfegh, K., Wuillemin, W. A., Redondo, M., Lammle, B., Beer, J., Liechti-Gallati, S., Meyer, B. J. (1999) Association of two silent polymorphisms of platelet glycoprotein la/lla receptor with risk of myocardial infarction: a case-control study Lancet 353,351-354[CrossRef][Medline]
    45. 45
  45. Roest, M., Banga, J. D., Grobbee, D. E., de Groot, P. G., Sixma, J. J., Tempelman, M. J., van der Schouw, Y. T. (2000) Homozygosity for 807 T polymorphism in {{alpha}}2 subunit of platelet {{alpha}}2{β}1 is associated with increased risk of cardiovascular mortality in high-risk women Circulation 102,1645-1650[Abstract/Free Full Text]
    46. 46
  46. Carlsson, L. E., Santoso, S., Spitzer, C., Kessler, C., Greinacher, A. (1999) The {alpha} 2 gene coding sequence T807/A873 of the platelet collagen receptor integrin {alpha} 2β 1 might be a genetic risk factor for the development of stroke in younger patients Blood 93,3583-3586[Abstract/Free Full Text]
    47. 47
  47. Bjorkbacka, H., Kunjathoor, V. V., Moore, K. J., Koehn, S., Ordija, C. M., Lee, M. A., Means, T., Halmen, K., Luster, A. D., Golenbock, D. T., Freeman, M. W. (2004) Reduced atherosclerosis in MyD88-null mice links elevated serum cholesterol levels to activation of innate immunity signaling pathways Nat. Med. 10,416-421[CrossRef][Medline]
    48. 48
  48. Wright, S. D., Burton, C., Hernandez, M., Hassing, H., Montenegro, J., Mundt, S., Patel, S., Card, D. J., Hermanowski-Vosatka, A., Bergstrom, J. D., et al (2000) Infectious agents are not necessary for murine atherogenesis J. Exp. Med. 191,1437-1442[Abstract/Free Full Text]
    49. 49
  49. Michelsen, K. S., Wong, M. H., Shah, P. K., Zhang, W., Yano, J., Doherty, T. M., Akira, S., Rajavashisth, T. B., Arditi, M. (2004) Lack of Toll-like receptor 4 or myeloid differentiation factor 88 reduces atherosclerosis and alters plaque phenotype in mice deficient in apolipoprotein E Proc. Natl. Acad. Sci. USA 101,10679-10684[Abstract/Free Full Text]
    50. 50
  50. Kiechl, S., Lorenz, E., Reindl, M., Wiedermann, C. J., Oberhollenzer, F., Bonora, E., Willeit, J., Schwartz, D. A. (2002) Toll-like receptor 4 polymorphisms and atherogenesis N. Engl. J. Med. 347,185-192[Abstract/Free Full Text]
    51. 51
  51. Ameziane, N., Beillat, T., Verpillat, P., Chollet-Martin, S., Aumont, M. C., Seknadji, P., Lamotte, M., Lebret, D., Ollivier, V., de Prost, D. (2003) Association of the Toll-like receptor 4 gene Asp299Gly polymorphism with acute coronary events Arterioscler. Thromb. Vasc. Biol. 23,e61-e64[Abstract/Free Full Text]
    52. 52
  52. Mullick, A. E., Tobias, P. S., Curtiss, L. K. (2005) Modulation of atherosclerosis in mice by Toll-like receptor 2 J. Clin. Invest. 115,3149-3156[CrossRef][Medline]
    53. 53
  53. Hamann, L., Gomma, A., Schroder, N. W., Stamme, C., Glaeser, C., Schulz, S., Gross, M., Anker, S. D., Fox, K., Schumann, R. R. (2005) A frequent Toll-like receptor (TLR)-2 polymorphism is a risk factor for coronary restenosis J. Mol. Med. 83,478-485[CrossRef][Medline]
    54. 54
  54. Ye, S., Eriksson, P., Hamsten, A., Kurkinen, M., Humphries, S. E., Henney, A. M. (1996) Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression J. Biol. Chem. 271,13055-13060[Abstract/Free Full Text]
    55. 55
  55. Ghilardi, G., Biondi, M. L., DeMonti, M., Turri, O., Guagnellini, E., Scorza, R. (2002) Matrix metalloproteinase-1 and matrix metalloproteinase-3 gene promoter polymorphisms are associated with carotid artery stenosis Stroke 33,2408-2412[Abstract/Free Full Text]
    56. 56
  56. Kuzuya, M., Nakamura, K., Sasaki, T., Wu Cheng, X., Itohara, S., Iguchi, A. (2006) Effect of MMP-2 deficiency on atherosclerotic lesion formation in ApoE-deficient mice Arterioscler. Thromb. Vasc. Biol. 26,1120-1125[Abstract/Free Full Text]
    57. 57
  57. Beyzade, S., Zhang, S., Wong, Y. K., Day, I. N., Eriksson, P., Ye, S. (2003) Influences of matrix metalloproteinase-3 gene variation on extent of coronary atherosclerosis and risk of myocardial infarction J. Am. Coll. Cardiol. 41,2130-2137[Abstract/Free Full Text]
    58. 58
  58. Terashima, M., Akita, H., Kanazawa, K., Inoue, N., Yamada, S., Ito, K., Matsuda, Y., Takai, E., Iwai, C., Kurogane, H., et al (1999) Stromelysin promoter 5A/6A polymorphism is associated with acute myocardial infarction Circulation 99,2717-2719[Abstract/Free Full Text]
    59. 59
  59. Luttun, A., Lutgens, E., Manderveld, A., Maris, K., Collen, D., Carmeliet, P., Moons, L. (2004) Loss of matrix metalloproteinase-9 or matrix metalloproteinase-12 protects apolipoprotein E-deficient mice against atherosclerotic media destruction but differentially affects plaque growth Circulation 109,1408-1414[Abstract/Free Full Text]
    60. 60
  60. Ye, S. (2006) Influence of matrix metalloproteinase genotype on cardiovascular disease susceptibility and outcome Cardiovasc. Res. 69,636-645[Abstract/Free Full Text]
    61. 61
  61. Murphy, P. M. (2002) International Union of Pharmacology. XXX. Update on chemokine receptor nomenclature Pharmacol. Rev. 54,227-229[Abstract/Free Full Text]
    62. 62
  62. Rollins, B. J. (2001) Chemokines and atherosclerosis: what Adam Smith has to say about vascular disease J. Clin. Invest. 108,1269-1271[CrossRef][Medline]
    63. 63
  63. Gu, L., Tseng, S. C., Rollins, B. J. (1999) Monocyte chemoattractant protein-1 Chem. Immunol. 72,7-29[Medline]
    64. 64
  64. Gu, L., Rutledge, B., Fiorillo, J., Ernst, C., Grewal, I., Flavell, R., Gladue, R., Rollins, B. (1997) In vivo properties of monocyte chemoattractant protein-1 J. Leukoc. Biol. 62,577-580[Abstract]
    65. 65
  65. Rollins, B. J. (1996) Monocyte chemoattractant protein 1: a potential regulator of monocyte recruitment in inflammatory disease Mol. Med. Today 2,198-204[CrossRef][Medline]
    66. 66
  66. Yla-Herttuala, S., Lipton, B. A., Rosenfeld, M. E., Sarkioja, T., Yoshimura, T., Leonard, E. J., Witztum, J. L., Steinberg, D. (1991) Expression of monocyte chemoattractant protein 1 in macrophage-rich areas of human and rabbit atherosclerotic lesions Proc. Natl. Acad. Sci. USA 88,5252-5256[Abstract/Free Full Text]
    67. 67
  67. Rayner, K., Van, E. S., Groot, P. H., Reape, T. J. (2000) Localization of mRNA for JE/MCP-1 and its receptor CCR2 in atherosclerotic lesions of the ApoE knockout mouse J. Vasc. Res. 37,93-102[CrossRef][Medline]
    68. 68
  68. Nelken, N. A., Coughlin, S. R., Gordon, D., Wilcox, J. N. (1991) Monocyte chemoattractant protein-1 in human atheromatous plaques J. Clin. Invest. 88,1121-1127[Medline]
    69. 69
  69. De Lemos, J. A., Morrow, D. A., Sabatine, M. S., Murphy, S. A., Gibson, C. M., Antman, E. M., McCabe, C. H., Cannon, C. P., Braunwald, E. (2003) Association between plasma levels of monocyte chemoattractant protein-1 and long-term clinical outcomes in patients with acute cororary syndromes Circulation 107,690-695[Abstract/Free Full Text]
    70. 70
  70. Aiello, R. J., Bourassa, P. A., Lindsey, S., Weng, W., Natoli, E., Rollins, B. J., Milos, P. M. (1999) Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice Arterioscler. Thromb. Vasc. Biol. 19,1518-1525[Abstract/Free Full Text]
    71. 71
  71. Boring, L., Gosling, J., Chensue, S. W., Kunkel, S. L., Farese, R. V., Jr, Broxmeyer, H. E., Charo, I. F. (1997) Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C–C chemokine receptor 2 knockout mice J. Clin. Invest. 100,2552-2561[Medline]
    72. 72
  72. Guo, J., Van Eck, M., Twisk, J., Maeda, N., Benson, G. M., Groot, P. H. E., Van Berkel, T. J. C. (2003) Transplantation of monocyte CC-chemokine receptor 2-deficient bone marrow into ApoE3-Leiden mice inhibits atherogenesis Arterioscler. Thromb. Vasc. Biol. 23,447-453[Abstract/Free Full Text]
    73. 73
  73. Kitamoto, S., Egashira, K. (2003) Anti-monocyte chemoattractant protein-1 gene therapy for cardiovascular diseases Expert Rev. Cardiovasc. Ther. 1,393-400[CrossRef][Medline]
    74. 74
  74. Egashira, K. (2003) Molecular mechanisms mediating inflammation in vascular disease: special reference to monocyte chemoattractant protein-1 Hypertension 41,834-841[Abstract/Free Full Text]
    75. 75
  75. Ni, W., Egashira, K., Kitamoto, S., Kataoka, C., Koyanagi, M., Inoue, S., Imaizumi, K., Akiyama, C., Nishida, K. I., Takeshita, A. (2001) New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice Circulation 103,2096-2101[Abstract/Free Full Text]
    76. 76
  76. Charo, I. F., Peters, W. (2003) Chemokine receptor 2 (CCR2) in atherosclerosis, infectious diseases, and regulation of T-cell polarization Microcirculation 10,259-264[CrossRef][Medline]
    77. 77
  77. Ross, R., Bowen-Pope, D., Raines, E. W., Faggiotto, A. (1982) Endothelial injury: blood-vessel wall interactions Ann. N. Y. Acad. Sci. 401,260-264[CrossRef][Medline]
    78. 78
  78. Ross, R., Faggiotto, A., Bowen-Pope, D., Raines, E. (1984) The role of endothelial injury and platelet and macrophage interactions in atherosclerosis Circulation 70,III77-III82[Medline]
    79. 79
  79. Witztum, J. L. (1994) The oxidation hypothesis of atherosclerosis Lancet 344,793-795[CrossRef][Medline]
    80. 80
  80. Han, K. H., Han, K. O., Green, S. R., Quehenberger, O. (1999) Expression of the monocyte chemoattractant protein-1 receptor CCR2 is increased in hypercholesterolemia: differential effects of plasma lipoproteins on monocyte function J. Lipid Res. 40,1053-1063[Abstract/Free Full Text]
    81. 81
  81. Han, K. H., Tangirala, R. K., Green, S. R., Quehenberger, O. (1998) Chemokine receptor CCR2 expression and monocyte chemoattractant protein-1-mediated chemotaxis in human monocytes: a regulatory role for plasma LDL Arterioscler. Thromb. Vasc. Biol. 18,1983-1991[Abstract/Free Full Text]
    82. 82
  82. Han, K. H., Chang, M. K., Boullier, A., Green, S. R., Li, A., Glass, C. K., Quehenberger, O. (2000) Oxidized LDL reduces monocyte CCR2 expression through pathways involving peroxisome proliferator-activated receptor {{gamma}} J. Clin. Invest. 106,793-802[Medline]
    83. 83
  83. Bazan, J. F., Bacon, K. B., Hardiman, G., Wang, W., Soo, K., Rossi, D., Greaves, D. R., Zlotnik, A., Schall, T. J. (1997) A new class of membrane-bound chemokine with a CX3C motif Nature 385,640-644[CrossRef][Medline]
    84. 84
  84. Imai, T., Hieshima, K., Haskell, C., Baba, M., Nagira, M., Nishimura, M., Kakizaki, M., Takagi, S., Nomiyama, H., Schall, T. J., Yoshie, O. (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion Cell 91,521-530[CrossRef][Medline]
    85. 85
  85. Garton, K. J., Gough, P. J., Blobel, C. P., Murphy, G., Greaves, D. R., Dempsey, P. J., Raines, E. W. (2001) Tumor necrosis factor-{alpha}-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1) J. Biol. Chem. 276,37993-38001[Abstract/Free Full Text]
    86. 86
  86. Hundhausen, C., Misztela, D., Berkhout, T. A., Broadway, N., Saftig, P., Reiss, K., Hartmann, D., Fahrenholz, F., Postina, R., Matthews, V., et al (2003) The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell–cell adhesion Blood 102,1186-1195[Abstract/Free Full Text]
    87. 87
  87. Wong, B. W. C., Wong, D., McManus, B. M. (2002) Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease Cardiovasc. Pathol. 11,332-338[CrossRef][Medline]
    88. 88
  88. Daoudi, M., Lavergne, E., Garin, A., Tarantino, N., Debre, P., Pincet, F., Combadiere, C., Deterre, P. (2004) Enhanced adhesive capacities of the naturally occurring Ile249-Met280 variant of the chemokine receptor CX3CR1 J. Biol. Chem. 279,19649-19657[Abstract/Free Full Text]
    89. 89
  89. Barlic, J., Zhang, Y., Foley, J. F., Murphy, P. M. (2006) Oxidized lipid-driven chemokine receptor switch, CCR2 to CX3CR1, mediates adhesion of human macrophages to coronary artery smooth muscle cells through a peroxisome proliferator-activated receptor {{gamma}}-dependent pathway Circulation 114,807-819[Abstract/Free Full Text]
    90. 90
  90. Morohashi, H., Miyawaki, T., Nomura, H., Kuno, K., Murakami, S., Matsushima, K., Mukaida, N. (1995) Expression of both types of human interleukin-8 receptors on mature neutrophils, monocytes, and natural killer cells J. Leukoc. Biol. 57,180-187[Abstract]
    91. 91
  91. Xu, L., Kelvin, D. J., Ye, G. Q., Taub, D. D., Ben-Baruch, A., Oppenheim, J. J., Wang, J. M. (1995) Modulation of IL-8 receptor expression on purified human T lymphocytes is associated with changed chemotactic responses to IL-8 J. Leukoc. Biol. 57,335-342[Abstract]
    92. 92
  92. Boisvert, W. A., Santiago, R., Curtiss, L. K., Terkeltaub, R. A. (1998) 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. 101,353-363[Medline]
    93. 93
  93. Apostolopoulos, J., Davenport, P., Tipping, P. G. (1996) Interleukin-8 production by macrophages from atheromatous plaques Arterioscler. Thromb. Vasc. Biol. 16,1007-1012[Abstract/Free Full Text]
    94. 94
  94. Bozic, C. R., Gerard, N. P., von Uexkull-Guldenband, C., Kolakowski, L. F., Jr, Conklyn, M. J., Breslow, R., Showell, H. J., Gerard, C. (1994) The murine interleukin 8 type B receptor homologue and its ligands. Expression and biological characterization J. Biol. Chem. 269,29355-29358[Abstract/Free Full Text]
    95. 95
  95. Huo, Y., Weber, C., Forlow, S. B., Sperandio, M., Thatte, J., Mack, M., Jung, S., Littman, D. R., Ley, K. (2001) The chemokine KC, but not monocyte chemoattractant protein-1, triggers monocyte arrest on early atherosclerotic endothelium J. Clin. Invest. 108,1307-1314[CrossRef][Medline]
    96. 96
  96. Lei, Z. B., Zhang, Z., Jing, Q., Qin, Y. W., Pei, G., Cao, B. Z., Li, X. Y. (2002) oxLDL upregulates CXCR2 expression in monocytes via scavenger receptors and activation of p38 mitogen-activated protein kinase Cardiovasc. Res. 53,524-532[Abstract/Free Full Text]
    97. 97
  97. Neumann, F. J., Ott, I., Gawaz, M., Richardt, G., Holzapfel, H., Jochum, M., Schomig, A. (1995) Cardiac release of cytokines and inflammatory responses in acute myocardial infarction Circulation 92,748-755[Abstract/Free Full Text]
    98. 98
  98. Yeh, M., Leitinger, N., de Martin, R., Onai, N., Matsushima, K., Vora, D. K., Berliner, J. A., Reddy, S. T. (2001) Increased transcription of IL-8 in endothelial cells is differentially regulated by TNF-{alpha} and oxidized phospholipids Arterioscler. Thromb. Vasc. Biol. 21,1585-1591[Abstract/Free Full Text]
    99. 99
  99. Duymaz-Tozkir, J., Yilmaz, V., Uyar, F. A., Hajeer, A. H., Saruhan-Direskeneli, G., Gul, A. (2005) Polymorphisms of the IL-8 and CXCR2 genes are not associated with Behcet’s disease J. Rheumatol. 32,93-97[Abstract/Free Full Text]
    100. 100
  100. Jensen, L. O., Thayssen, P., Pedersen, K. E., Stender, S., Haghfelt, T. (2004) Regression of coronary atherosclerosis by simvastatin: a serial intravascular ultrasound study Circulation 110,265-270[Abstract/Free Full Text]
    101. 101
  101. Corti, R., Fuster, V., Fayad, Z. A., Worthley, S. G., Helft, G., Smith, D., Weinberger, J., Wentzel, J., Mizsei, G., Mercuri, M., Badimon, J. J. (2002) Lipid lowering by simvastatin induces regression of human atherosclerotic lesions: two years’ follow-up by high-resolution noninvasive magnetic resonance imaging Circulation 106,2884-2887[Abstract/Free Full Text]
    102. 102
  102. Navab, M., Anantharamaiah, G. M., Reddy, S. T., Fogelman, A. M. (2006) Apolipoprotein A-I mimetic peptides and their role in atherosclerosis prevention Nat. Clin. Pract. Cardiovasc. Med. 3,540-547[CrossRef][Medline]
    103. 103
  103. Nissen, S. E., Tsunoda, T., Tuzcu, E. M., Schoenhagen, P., Cooper, C. J., Yasin, M., Eaton, G. M., Lauer, M. A., Sheldon, W. S., Grines, C. L., et al (2003) Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial JAMA 290,2292-2300[Abstract/Free Full Text]
    104. 104
  104. Rong, J. X., Li, J., Reis, E. D., Choudhury, R. P., Dansky, H. M., Elmalem, V. I., Fallon, J. T., Breslow, J. L., Fisher, E. A. (2001) Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content Circulation 104,2447-2452[Abstract/Free Full Text]
    105. 105
  105. Reis, E. D., Li, J., Fayad, Z. A., Rong, J. X., Hansoty, D., Aguinaldo, J. G., Fallon, J. T., Fisher, E. A. (2001) Dramatic remodeling of advanced atherosclerotic plaques of the apolipoprotein E-deficient mouse in a novel transplantation model J. Vasc. Surg. 34,541-547[CrossRef][Medline]
    106. 106
  106. Llodra, J., Angeli, V., Liu, J., Trogan, E., Fisher, E. A., Randolph, G. J. (2004) From the cover: emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive, plaques Proc. Natl. Acad. Sci. USA 101,11779-11784[Abstract/Free Full Text]
    107. 107
  107. Trogan, E., Feig, J. E., Dogan, S., Rothblat, G. H., Angeli, V., Tacke, F., Randolph, G. J., Fisher, E. A. (2006) Gene expression changes in foam cells and the role of chemokine receptor CCR7 during atherosclerosis regression in ApoE-deficient mice Proc. Natl. Acad. Sci. USA 103,3781-3786[Abstract/Free Full Text]
    108. 108
  108. Wilbanks, A., Zondlo, S. C., Murphy, K., Mak, S., Soler, D., Langdon, P., Andrew, D. P., Wu, L., Briskin, M. (2001) Expression cloning of the STRL33/BONZO/TYMSTR ligand reveals elements of CC, CXC, and CX3C chemokines J. Immunol. 166,5145-5154[Abstract/Free Full Text]
    109. 109
  109. Shimaoka, T., Nakayama, T., Fukumoto, N., Kume, N., Takahashi, S., Yamaguchi, J., Minami, M., Hayashida, K., Kita, T., Ohsumi, J., et al (2004) Cell surface-anchored SR-PSOX/CXC chemokine ligand 16 mediates firm adhesion of CXC chemokine receptor 6-expressing cells J. Leukoc. Biol. 75,267-274[Abstract/Free Full Text]
    110. 110
  110. Gough, P. J., Garton, K. J., Wille, P. T., Rychlewski, M., Dempsey, P. J., Raines, E. W. (2004) A disintegrin and metalloproteinase 10-mediated cleavage and shedding regulates the cell surface expression of CXC chemokine ligand 16 J. Immunol. 172,3678-3685[Abstract/Free Full Text]
    111. 111
  111. Fukumoto, N., Shimaoka, T., Fujimura, H., Sakoda, S., Tanaka, M., Kita, T., Yonehara, S. (2004) Critical roles of CXC chemokine ligand 16/scavenger receptor that binds phosphatidylserine and oxidized lipoprotein in the pathogenesis of both acute and adoptive transfer experimental autoimmune encephalomyelitis J. Immunol. 173,1620-1627[Abstract/Free Full Text]
    112. 112
  112. Minami, M., Kume, N., Shimaoka, T., Kataoka, H., Hayashida, K., Akiyama, Y., Nagata, I., Ando, K., Nobuyoshi, M., Hanyuu, M., et al (2001) Expression of SR-PSOX, a novel cell-surface scavenger receptor for phosphatidylserine and oxidized LDL in human atherosclerotic lesions Arterioscler. Thromb. Vasc. Biol. 21,1796-1800[Abstract/Free Full Text]
    113. 113
  113. Minami, M., Kume, N., Shimaoka, T., Kataoka, H., Hayashida, K., Yonehara, S., Kita, T. (2001) Expression of scavenger receptor for phosphatidylserine and oxidized lipoprotein (SR-PSOX) in human atheroma Ann. N. Y. Acad. Sci. 947,373-376[Medline]
    114. 114
  114. Wuttge, D. M., Zhou, X., Sheikine, Y., Wagsater, D., Stemme, V., Hedin, U., Stemme, S., Hansson, G. K., Sirsjo, A. (2004) CXCL16/SR-PSOX is an interferon-{{gamma}}-regulated chemokine and scavenger receptor expressed in atherosclerotic lesions Arterioscler. Thromb. Vasc. Biol. 24,750-755[Abstract/Free Full Text]
    115. 115
  115. Sheikine, Y., Bang, C. S., Nilsson, L., Samnegard, A., Hamsten, A., Jonasson, L., Eriksson, P., Sirsjo, A. (2006) Decreased plasma CXCL16/SR-PSOX concentration is associated with coronary artery disease Atherosclerosis 188,462-466[CrossRef][Medline]
    116. 116
  116. Sheikine, Y., Bang, C. S., Sirsjo, A. (2006) Can CXCL16 be linked to coronary vascular disease? We still know too little Atherosclerosis 189,472-473[CrossRef]
    117. 117
  117. Schecter, A. D., Berman, A. B., Taubman, M. B. (2003) Chemokine receptors in vascular smooth muscle Microcirculation 10,265-272[CrossRef][Medline]
    118. 118
  118. Schwartz, S. M., deBlois, D., O’Brien, E. R. M. (1995) The intima: soil for atherosclerosis and restenosis Circ. Res. 77,445-465[Free Full Text]
    119. 119
  119. Rakesh, K., Agrawal, D. K. (2005) Cytokines and growth factors involved in apoptosis and proliferation of vascular smooth muscle cells Int. Immunopharmacol. 5,1487-1506[CrossRef][Medline]
    120. 120
  120. Schecter, A. D., Calderon, T. M., Berman, A. B., McManus, C. M., Fallon, J. T., Rossikhina, M., Zhao, W., Christ, G., Berman, J. W., Taubman, M. B. (2000) Human vascular smooth muscle cells possess functional CCR5 J. Biol. Chem. 275,5466-5471[Abstract/Free Full Text]
    121. 121
  121. Hayes, I. M., Jordan, N. J., Towers, S., Smith, G., Paterson, J. R., Earnshaw, J. J., Roach, A. G., Westwick, J., Williams, R. J. (1998) Human vascular smooth muscle cells express receptors for CC chemokines Arterioscler. Thromb. Vasc. Biol. 18,397-403[Abstract/Free Full Text]
    122. 122
  122. Roque, M., Kim, W. J. H., Gazdoin, M., Malik, A., Reis, E. D., Fallon, J. T., Badimon, J. J., Charo, I. F., Taubman, M. B. (2002) CCR2 deficiency decreases intimal hyperplasia after arterial injury Arterioscler. Thromb. Vasc. Biol. 22,554-559[Abstract/Free Full Text]
    123. 123
  123. Lucas, A. D., Bursill, C., Guzik, T. J., Sadowski, J., Channon, K. M., Greaves, D. R. (2003) Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1) Circulation 108,2498-2504[Abstract/Free Full Text]
    124. 124
  124. Liu, P., Patil, S., Rojas, M., Fong, A. M., Smyth, S. S., Patel, D. D. (2006) CX3CR1 deficiency confers protection from intimal hyperplasia after arterial injury Arterioscler. Thromb. Vasc. Biol. 26,2056-2062[Abstract/Free Full Text]
    125. 125
  125. Haque, N. S., Fallon, J. T., Pan, J. J., Taubman, M. B., Harpel, P. C. (2004) Chemokine receptor-8 (CCR8) mediates human vascular smooth muscle cell chemotaxis and metalloproteinase-2 secretion Blood 103,1296-1304[Abstract/Free Full Text]
    126. 126
  126. Haque, N. S., Zhang, X., French, D. L., Li, J., Poon, M., Fallon, J. T., Gabel, B. R., Taubman, M. B., Koschinsky, M., Harpel, P. C. (2000) CC chemokine I-309 is the principal monocyte chemoattractant induced by apolipoprotein(a) in human vascular endothelial cells Circulation 102,786-792[Abstract/Free Full Text]
    127. 127
  127. Yue, T. L., Wang, X., Sung, C. P., Olson, B., McKenna, P. J., Gu, J. L., Feuerstein, G. Z. (1994) Interleukin-8. A mitogen and chemoattractant for vascular smooth muscle cells Circ. Res. 75,1-7[Abstract/Free Full Text]
    128. 128
  128. Wagsater, D., Olofsson, P. S., Norgren, L., Stenberg, B., Sirsjo, A. (2004) The chemokine and scavenger receptor CXCL16/SR-PSOX is expressed in human vascular smooth muscle cells and is induced by interferon [{gamma}] Biochem. Biophys. Res. Commun. 325,1187-1193[CrossRef][Medline]
    129. 129
  129. Hansson, G. K., Libby, P. (2006) The immune response in atherosclerosis: a double-edged sword Nat. Rev. Immunol. 6,508-519[CrossRef][Medline]
    130. 130
  130. Robertson, A. K., Hansson, G. K. (2006) T cells in atherogenesis: for better or for worse? Arterioscler. Thromb. Vasc. Biol. 26,2421-2432[Abstract/Free Full Text]
    131. 131
  131. Farber, J. M. (1997) Mig and IP-10: CXC chemokines that target lymphocytes J. Leukoc. Biol. 61,246-257[Abstract]
    132. 132
  132. Mach, F., Sauty, A., Iarossi, A. S., Sukhova, G. K., Neote, K., Libby, P., Luster, A. D. (1999) Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells J. Clin. Invest. 104,1041-1050[Medline]
    133. 133
  133. Cheong, H. S., Park, C. S., Kim, L. H., Park, B. L., Uh, S. T., Kim, Y. H., Lym, G. I., Lee, J. Y., Lee, J. K., Kim, H. T., et al (2005) CXCR3 polymorphisms associated with risk of asthma Biochem. Biophys. Res. Commun. 334,1219-1225[CrossRef][Medline]
    134. 134
  134. Venturelli, E., Galimberti, D., Fenoglio, C., Lovati, C., Finazzi, D., Guidi, I., Corra, B., Scalabrini, D., Clerici, F., Mariani, C., Forloni, G., Bresolin, N., Scarpini, E. (2006) Candidate gene analysis of IP-10 gene in patients with Alzheimer’s disease Neurosci. Lett. 404,217-221[CrossRef][Medline]
    135. 135
  135. Zhang, J., Noguchi, E., Migita, O., Yokouchi, Y., Nakayama, J., Shibasaki, M., Arinami, T. (2005) Association of a haplotype block spanning SDAD1 gene and CXC chemokine genes with allergic rhinitis J. Allergy Clin. Immunol. 115,548-554[CrossRef][Medline]
    136. 136
  136. Veillard, N. R., Kwak, B., Pelli, G., Mulhaupt, F., James, R. W., Proudfoot, A. E. I., Mach, F. (2004) Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice Circ. Res. 94,253-261[Abstract/Free Full Text]
    137. 137
  137. Pattison, J. M., Nelson, P. J., Huie, P., Sibley, R. K., Krensky, A. M. (1996) RANTES chemokine expression in transplant-associated accelerated atherosclerosis J. Heart Lung Transplant. 15,1194-1199[Medline]
    138. 138
  138. Von Luettichau, I., Nelson, P. J., Pattison, J. M., van de Rijn, M., Huie, P., Warnke, R., Wiedermann, C. J., Stahl, R. A., Sibley, R. K., Krensky, A. M. (1996) RANTES chemokine expression in diseased and normal human tissues Cytokine 8,89-98[CrossRef][Medline]
    139. 139
  139. Liu, H., Chao, D., Nakayama, E. E., Taguchi, H., Goto, M., Xin, X., Takamatsu, J. K., Saito, H., Ishikawa, Y., Akaza, T., Juji, T., Takebe, Y., Ohishi, T., Fukutake, K., Maruyama, Y., Yashiki, S., Sonoda, S., Nakamura, T., Nagai, Y., Iwamoto, A., Shioda, T. (1999) Polymorphism in chemokine promoter affects HIV-1 disease progression Proc. Natl. Acad. Sci. USA 96,4581-4585[Abstract/Free Full Text]
    140. 140
  140. Nickel, R. G., Casolaro, V., Wahn, U., Beyer, K., Barnes, K. C., Plunkett, B. S., Freidhoff, L. R., Sengler, C., Plitt, J. R., Schleimer, R. P., et al (2000) Atopic dermatitis is associated with a functional mutation in the promoter of the C–C chemokine RANTES J. Immunol. 164,1612-1616[Abstract/Free Full Text]
    141. 141
  141. Simeoni, E., Winkelmann, B. R., Hoffmann, M. M., Fleury, S., Ruiz, J., Kappenberger, L., Marz, W., Vassalli, G. (2004) Association of RANTES G-403A gene polymorphism with increased risk of coronary arteriosclerosis Eur. Heart J. 25,1438-1446[Abstract/Free Full Text]



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