Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo

Veillard, Niels R.; Steffens, Sabine; Pelli, Graziano; Liu, Bao; Kwak, Brenda R.; Gérard, Craig; Charo, Israel F.; Mach, François

doi:10.1161/circulationaha.104.520718

Cited by 128 publications

(107 citation statements)

References 38 publications

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“…An example for CCR2 (the receptor for MCP-1) was given in the introduction. In another study, there was a clearly protective effect of heterozygous CXCR3 deficiency for early atherosclerosis but none for more advanced lesions (1871). In contrast, for CX3CR1 (the fractalkine receptor), heterozygous deficiency resulted in as great a reduction in atherosclerosis as complete deficiency, suggesting a sort of redundancy even in the number of alleles (344).…”

Section: G Redundancy In Leukocyte Signalingmentioning

confidence: 96%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: G Redundancy In Leukocyte Signalingmentioning

confidence: 96%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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“…Expression of MCP-1 by a subset of cells in atherosclerotic lesions suggests active recruitment of monocytes to developing lesions in vivo (31,32), and mice lacking MCP-1 or C-C motif chemokine receptor 2 (CCR2) show reduced atherosclerosis (33)(34)(35). Thus monocyte recruitment into lesions may require CCR2 expression, a feature of the Ly-6C hi subtype (19).…”

Section: Figurementioning

confidence: 99%

Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata

Świrski¹,

Libby²,

Aikawa³

et al. 2007

J. Clin. Invest.

1,113

1,083

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Macrophage accumulation participates decisively in the development and exacerbation of atherosclerosis. Circulating monocytes, the precursors of macrophages, display heterogeneity in mice and humans, but their relative contribution to atherogenesis remains unknown. We report here that the Ly-6C hi monocyte subset increased dramatically in hypercholesterolemic apoE-deficient mice consuming a high-fat diet, with the number of Ly-6C hi cells doubling in the blood every month. Ly-6C hi monocytes adhered to activated endothelium, infiltrated lesions, and became lesional macrophages. Hypercholesterolemia-associated monocytosis (HAM) developed from increased survival, continued cell proliferation, and impaired Ly-6C hi to Ly-6C lo conversion and subsided upon statin-induced cholesterol reduction. Conversely, the number of Ly-6C lo cells remained unaffected. Thus, we believe that Ly-6C hi monocytes represent a newly recognized component of the inflammatory response in experimental atherosclerosis.

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“…1 So far, there are no data showing that an inhibition of T-cell migration directly influences atherogenesis, but various groups have demonstrated that a reduction of the expression of T-cell-specific chemokines hampers plaque formation. 2,3 Thus, it may be assumed that modulating the migration of T-lymphocytes into the vasculature may also target the inflammatory process in atherogenesis at a nodal point and, as such, address a critical step in lesion development. Still, recent data by Ait-Oufella et al 29 have shown that a subset of CD4-positive lymphocytes, named natural regulatory cells (CD4 ϩ /CD25 ϩ regulatory T cells), may exhibit atheroprotective effects, raising the question of whether an inhibition of CD4-lymphocyte migration may be protective under all circumstances.…”

Section: Walcher Et Al Telmisartan Inhibits Lymphocyte Migrationmentioning

confidence: 99%

“…It is unclear whether an inhibition of cell migration itself modulates vascular disease, but various experimental studies have shown that a reduction in CD4-positive lymphocyte recruitment hampers lesion development and plaque formation. 2,3 Still, most of these studies targeted the effect of T-cell-specific chemokines, but hitherto little is known about modulatory effects on CD4-positive lymphocyte migration.…”

mentioning

confidence: 99%

Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-γ

et al. 2008

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Abstract-Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis.Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-␥-activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPAR␥ in this context. CD4-positive lymphocytes express both the AT1R and PPAR␥. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1Ϯ3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6Ϯ0.7-fold induction at 10 mol/L of telmisartan (PϽ0.01 compared with SDF-1-treated cells; nϭ22). Three different PPAR␥ activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPAR␥-activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan's effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPAR␥ small interfering RNA abolished telmisartan's effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPAR␥. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPAR␥-activating properties. Key Words: telmisartan Ⅲ PPAR␥ Ⅲ angiotensin type 1 receptor blocker Ⅲ CD4-positive lymphocytes Ⅲ migration A therogenesis is an inflammatory process in the vessel wall involving inflammatory cells like monocytes, macrophages, and CD4-positive lymphocytes. 1 In early atherogenesis, CD4-positive lymphocytes are attracted by chemotactic proteins, such as regulated upon activation, normal T-cell expressed, and secreted (RANTES) and stromal cellderived factor (SDF)-1 and enter the vessel wall as naïve T-helper 0 cells. In the subendothelium, these cells then encounter antigens like oxidized low-density lipoprotein and differentiate into T-helper 1 cells, subsequently releasing proinflammatory mediators like tumor necrosis factor-␣ and interferon-␥. These cytokines then govern the inflammatory response in the vessel wall by activating other cells, such as endothelial cells, macrophages, and vascular smooth muscle cells, thus promoting the inflammatory process in atherogenesis. It is unclear whether an inhibition of cell migration itself modulates vascular disease, but various experimental studies have shown that a reduction in CD4-positive lymphocyte recruitment hampers lesion development and plaque formation. 2,3 Still, most of these studies targeted the effect of T-cell-specific chemokines, but hitherto little is known about modulatory effects on CD4-positive lymphocyte migration.T...

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Differential Influence of Chemokine Receptors CCR2 and CXCR3 in Development of Atherosclerosis In Vivo

Cited by 128 publications

References 38 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

Ly-6Chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata

Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-γ

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