Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age

Ortlepp, Jan R.; Vesper, Katharina; Mevissen, Vera; Schmitz, Fabian; Janssens, Uwe; Franke, Andreas; Hanrath, Peter; Weber, Christian; Zerres, Klaus; Hoffmann, Rainer

doi:10.1007/s00109-003-0435-x

Cited by 68 publications

(53 citation statements)

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“…One common variant in CCR2, Val64Ile (rs1799864), has been associated with coronary artery calcium with the rarer 64Ile allele associated with decreased coronary artery calcium independent of sex and other traditional risk factors. 19 This allele has also been associated with early-onset MI 20,21 and heart failure but not coronary atherosclerosis suggesting a less stable plaque morphology due to lack of calcification that may explain increased risk of MI observed in carriers of 64Ile. 20 However, the Val64Ile allele was not associated with MI in a retrospective study of patients in Iceland who survived an MI at 37-69 years of age.…”

Section: Discussionmentioning

confidence: 99%

“…19 This allele has also been associated with early-onset MI 20,21 and heart failure but not coronary atherosclerosis suggesting a less stable plaque morphology due to lack of calcification that may explain increased risk of MI observed in carriers of 64Ile. 20 However, the Val64Ile allele was not associated with MI in a retrospective study of patients in Iceland who survived an MI at 37-69 years of age. 22 Two isoforms of the receptor, CCR2A and CCR2B, are the result of alternative splicing.…”

Section: Discussionmentioning

confidence: 99%

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Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

et al. 2007

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Atherogenesis is a chronic inflammatory process. Critical in the inflammation process is monocyte chemoattractant protein-1 (MCP-1). To locate genomic regions that affect circulating MCP-1 levels, a genome-wide linkage scan was conducted in a sample of whites and blacks. Phenotype and genetic marker data were available for 2501 white and 513 black participants in the National Heart Lung Blood Institute Family Heart Study follow-up examination. Heritability for MCP-1 was 0.37 in whites and 0.47 in blacks after adjusting for the effects of sex, age, age-sex interaction, smoking status, lifetime smoking exposure (pack-years) and field center. Significant linkage was observed for MCP-1 in a combined black and white sample on chromosome 3 (logarithm of the odds ratio (LOD) ¼ 3.5 at 78 cM, P ¼ 0.0001) and suggestive linkage was observed in whites on chromosome 5 (LOD ¼ 1.8 at 128 cM, P ¼ 0.002). Located under the linkage peak on chromosome 3 is the chemokine receptor gene cluster, including CCR2, the receptor for MCP-1. This study provides preliminary evidence linking genetic variation in a receptor to circulating levels of its ligand, as previously demonstrated for the low-density lipoprotein receptor. Further characterization of these chromosomal regions is needed to identify the functional mutations associated with circulating levels of MCP-1.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

et al. 2007

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“…In healthy subjects with a family history of heart disease, both 76 In another study, the 64I mutation was associated with myocardial infarction or reduced left ventricular function in patients aged 65 years or younger, suggesting that the mutation may be deleterious. 77 However, the 64I allele was not associated with coronary artery atherosclerosis, which may indicate that the effects of CCR2 are more related to plaque stability than to plaque size as measured by angiography. Evidence for a role for MCP-1 in ischemic heart disease comes from a study of plasma MCP-1 levels in healthy volunteers and patients with acute coronary syndrome.…”

Section: Arteriogenesismentioning

confidence: 96%

Chemokines in the Pathogenesis of Vascular Disease

Charo

Taubman

2004

Circulation Research

671

511

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Abstract-Our increasing appreciation of the importance of inflammation in vascular disease has focused attention on the molecules that direct the migration of leukocytes from the blood stream to the vessel wall. In this review, we summarize roles of the chemokines, a family of small secreted proteins that selectively recruit monocytes, neutrophils, and lymphocytes to sites of vascular injury, inflammation, and developing atherosclerosis. Chemokines induce chemotaxis through the activation of G-protein-coupled receptors, and the receptors that a given leukocyte expresses determines the chemokines to which it will respond. Monocyte chemoattractant protein 1 (MCP-1), acting through its receptor CCR2, appears to play an early and important role in the recruitment of monocytes to atherosclerotic lesions and in the formation of intimal hyperplasia after arterial injury. Acute thrombosis is an often fatal complication of atherosclerotic plaque rupture, and recent evidence suggests that MCP-1 contributes to thrombin generation and thrombus formation by generating tissue factor. Because of their critical roles in monocyte recruitment in vascular and nonvascular diseases, MCP-1 and CCR2 have become important therapeutic targets, and efforts are underway to develop potent and specific antagonists of these and related chemokines. A preponderance of evidence from clinical and experimental studies supports the notion that inflammation plays an important role in a wide range of cardiovascular diseases [1][2][3][4] and has focused attention on the signals that initiate cellular infiltration of vascular tissues. The chemokines are a family of potent chemotactic cytokines that regulate the trafficking of leukocytes and are rapidly upregulated at sites of vascular inflammation. Here, we review the role of monocyte chemoattractant protein 1 (MCP-1) and related chemokines in regulating the recruitment of monocyte/macrophages to the vessel wall and discuss how these chemokines contribute to the pathophysiology of vascular disease, with an emphasis on atherosclerosis. Chemokines and Chemokine ReceptorsChemokines (chemotactic cytokines) are small heparinbinding proteins that direct the migration of circulating leukocytes to sites of inflammation or injury. 5,6 There are Ϸ50 human chemokines, which are divided into three major families based on differences in their structure and function.The largest family is known as the CC chemokines because the first two of the four conserved cysteine residues that are characteristic of chemokines are adjacent to each other. CC chemokines tend to attract mononuclear cells and are found at sites of chronic inflammation. The most thoroughly characterized CC chemokine is MCP-1 (also known as CCL2), a potent agonist for monocytes, memory T cells, and basophils. The third family, the CX3C family, has only one known member, fractalkine (FK; or CX3CL1). FK consists of a soluble chemokine domain fused to a mucin-like stalk and a transmembrane domain. Thus, unlike other soluble chemokines, it is a type 1 tran...

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“…At the center of this disease process is recruitment of circulating monocytes into the injured vascular wall. In human subjects, polymorphisms in the chemokine receptors CCR2 and CX 3 CR1, which result in reduced chemotaxis of monocytes, are highly protective against adverse cardiovascular events (3,4). Mice deficient in CCR2, CX 3 CR1, and CCR5 demonstrate decreased monocyte trafficking into vascular lesions, and combined blockade of all three confers additive protection (5)(6)(7)(8)(9).…”

Section: †mentioning

confidence: 99%

The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells

Mukovozov

Huang

Zhang

et al. 2015

The Journal of Immunology

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The secreted neurorepellent Slit2, acting through its transmembrane receptor, Roundabout (Robo)-1, inhibits chemotaxis of varied cell types, including leukocytes, endothelial cells, and vascular smooth muscle cells, toward diverse attractants. The role of Slit2 in regulating the steps involved in recruitment of monocytes in vascular inflammation is not well understood. In this study, we showed that Slit2 inhibited adhesion of monocytic cells to activated human endothelial cells, as well as to immobilized ICAM-1 and VCAM-1. Microfluidic live cell imaging showed that Slit2 inhibited the ability of monocytes tethered to endothelial cells to stabilize their actin-associated anchors and to resist detachment in response to increasing shear forces. Transfection of constitutively active plasmids revealed that Slit2 inhibited postadhesion stabilization of monocytes on endothelial cells by preventing activation of Rac1. We further found that Slit2 inhibited chemotaxis of monocytes toward CXCL12 and CCL2. To determine whether Slit2 and Robo-1 modulate pathologic monocyte recruitment associated with vascular inflammation and cardiovascular disease, we tested PBMC from patients with coronary artery disease. PBMC from these patients had reduced surface levels of Robo-1 compared with healthy age- and sex-matched subjects, and Slit2 failed to inhibit chemotaxis of PBMC of affected patients, but not healthy control subjects, toward CCL2. Furthermore, administration of Slit2 to atherosclerosis-prone LDL receptor–deficient mice inhibited monocyte recruitment to nascent atherosclerotic lesions. These results demonstrate that Slit2 inhibits chemotaxis of monocytes, as well as their ability to stabilize adhesions and resist detachment forces. Slit2 may represent a powerful new tool to inhibit pathologic monocyte recruitment in vascular inflammation and atherosclerosis.

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Chemokine receptor (CCR2) genotype is associated with myocardial infarction and heart failure in patients under 65 years of age

Cited by 68 publications

References 11 publications

Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

Circulating MCP-1 levels shows linkage to chemokine receptor gene cluster on chromosome 3: the NHLBI Family Heart Study follow-up examination

Chemokines in the Pathogenesis of Vascular Disease

The Neurorepellent Slit2 Inhibits Postadhesion Stabilization of Monocytes Tethered to Vascular Endothelial Cells

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