Experimental and Molecular Pathology

2007

DOI: 10.1016/j.yexmp.2006.10.008

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Accumulation of immune cells and high expression of chemokines/chemokine receptors in the upstream shoulder of atherosclerotic carotid plaques

¹

,

Bettina Lipfert

²

,

³

et al.

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Clinical Perspective On P 21381

Dcs and Atherosclerosis1

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Cited by 48 publications

(47 citation statements)

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“…45 However, studies that early identified the expression of several chemokines chemoattractans for lymphocytes in carotid specimens from patients subjected to endarterectomy 46 failed to detect CCL20 by conventional PCR or in situ hybridization. Most recently, however, Yilmaz et al 47 described the presence of CCL20 in carotid plaques associated with inflammatory cells. In the present study, we detected a strong upregulation of CCL20 in human atherosclerotic lesions from CAD patients suggesting an active role of the CCL20/CCR6 system in atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells

¹

,

Rodríguez-Calvo

²

,

³

et al. 2011

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Objective-Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC). Methods and Results-In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5Ϯ3.2 versus 9.1Ϯ1.3 pg/mL; PϽ0.01). LDL induced the expression of CCL20 in VSMC in a dose-and time-dependent manner. Increased levels of CCL20 secreted by LDL-treated VSMC significantly induced human lymphocyte migration, an effect reduced by CCL20 silencing. The upregulation of CCL20 by LDL was dependent on the activation of kinase signaling pathways and NF-B. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-B site (Ϫ80/Ϫ71) in CCL20 promoter critical for LDL responsiveness. Lysophosphatidic acid mimicked the upregulation of CCL20 induced by LDL, and minimal oxidation of LDL increased the ability of LDL to induce CCL20 through a mechanism that involves lysophosphatidic acid receptors. CCL20 was overexpressed in atherosclerotic lesions from coronary artery patients, colocalizing with VSMC. CCL20 was detected in conditioned media from healthy human aorta and its levels were significantly higher in secretomes from carotid endarterectomy specimens. A therosclerosis is essentially an inflammatory chronic disease. [1][2][3] Inflammation is a necessary response to injury and infection. Virtually all cardiovascular risk factors are capable of promoting an inflammatory response; among them, however, elevated levels of plasma cholesterol, in particular LDL, are recognized as one of the most important risk factors for atherosclerosis. 4,5 The inflammatory response involves the coordinated regulation of cell adhesion and migration and the establishment of a chemotactic gradient that guides inflammatory cells to damaged tissues. Key elements in this communication network are cytokines and chemokines, which orchestrate the recruitment, survival, expansion, and effector function of inflammatory cells. 6 -8 Chemokines are a superfamily of structurally related small chemotactic cytokines that control leukocyte function through interactions with their cognate 7-transmembranedomain G protein-coupled receptors. Monocytes/macrophages and T lymphocytes are the most abundant inflammatory cells found in atherosclerotic plaques, 9,10 but also B cells, dendritic cells, and neutrophils contribute to the pathogenesis of atherosclerosis. 9,11,12 Native and modified LDL modulate the expression of key genes involved in the recruitment and trafficking of inflammatory cells including cellular adhesion molecules and chemokines such as monocyte chemotactic protein 1. 4,5,[13][14][15] Recent studies have implicated other chemokines in atherosclerosis and have extended the knowledge about the regulation of chemokines/chemokine receptors on vascular cells, 6 -8 but the complete picture of these molecules involved in atherogenesis is not completely understood. Conclusion-ThisIncreasing data involving innate and adapti...

“…45 However, studies that early identified the expression of several chemokines chemoattractans for lymphocytes in carotid specimens from patients subjected to endarterectomy 46 failed to detect CCL20 by conventional PCR or in situ hybridization. Most recently, however, Yilmaz et al 47 described the presence of CCL20 in carotid plaques associated with inflammatory cells. In the present study, we detected a strong upregulation of CCL20 in human atherosclerotic lesions from CAD patients suggesting an active role of the CCL20/CCR6 system in atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

CCL20 Is Increased in Hypercholesterolemic Subjects and Is Upregulated By LDL in Vascular Smooth Muscle Cells

¹

,

Rodríguez-Calvo

²

,

³

et al. 2011

View full text Add to dashboard Cite

Objective-Our aim was to analyze the regulation of CC Chemokine ligand 20 (CCL20) by LDL in human vascular smooth muscle cells (VSMC). Methods and Results-In asymptomatic subjects, circulating CCL20 levels were higher in patients with hypercholesterolemia (18.5Ϯ3.2 versus 9.1Ϯ1.3 pg/mL; PϽ0.01). LDL induced the expression of CCL20 in VSMC in a dose-and time-dependent manner. Increased levels of CCL20 secreted by LDL-treated VSMC significantly induced human lymphocyte migration, an effect reduced by CCL20 silencing. The upregulation of CCL20 by LDL was dependent on the activation of kinase signaling pathways and NF-B. By site-directed mutagenesis, electrophoretic mobility shift assay, and chromatin immunoprecipitation, we identified a NF-B site (Ϫ80/Ϫ71) in CCL20 promoter critical for LDL responsiveness. Lysophosphatidic acid mimicked the upregulation of CCL20 induced by LDL, and minimal oxidation of LDL increased the ability of LDL to induce CCL20 through a mechanism that involves lysophosphatidic acid receptors. CCL20 was overexpressed in atherosclerotic lesions from coronary artery patients, colocalizing with VSMC. CCL20 was detected in conditioned media from healthy human aorta and its levels were significantly higher in secretomes from carotid endarterectomy specimens. A therosclerosis is essentially an inflammatory chronic disease. [1][2][3] Inflammation is a necessary response to injury and infection. Virtually all cardiovascular risk factors are capable of promoting an inflammatory response; among them, however, elevated levels of plasma cholesterol, in particular LDL, are recognized as one of the most important risk factors for atherosclerosis. 4,5 The inflammatory response involves the coordinated regulation of cell adhesion and migration and the establishment of a chemotactic gradient that guides inflammatory cells to damaged tissues. Key elements in this communication network are cytokines and chemokines, which orchestrate the recruitment, survival, expansion, and effector function of inflammatory cells. 6 -8 Chemokines are a superfamily of structurally related small chemotactic cytokines that control leukocyte function through interactions with their cognate 7-transmembranedomain G protein-coupled receptors. Monocytes/macrophages and T lymphocytes are the most abundant inflammatory cells found in atherosclerotic plaques, 9,10 but also B cells, dendritic cells, and neutrophils contribute to the pathogenesis of atherosclerosis. 9,11,12 Native and modified LDL modulate the expression of key genes involved in the recruitment and trafficking of inflammatory cells including cellular adhesion molecules and chemokines such as monocyte chemotactic protein 1. 4,5,[13][14][15] Recent studies have implicated other chemokines in atherosclerosis and have extended the knowledge about the regulation of chemokines/chemokine receptors on vascular cells, 6 -8 but the complete picture of these molecules involved in atherogenesis is not completely understood. Conclusion-ThisIncreasing data involving innate and adapti...

“…18,19 In addition, certain studies have investigated the possibility that lesion microvessels could be involved in the delivery of leukocytes to plaque. 20 However, the functional characteristics of microvessels in atherosclerotic lesions, including their inflammatory properties, are unknown, and direct evidence for the roles of microvessels in the accumulation of leukocytes in lesions is missing.…”

Section: Clinical Perspective On P 2138mentioning

confidence: 99%

Intravital Microscopy on Atherosclerosis in Apolipoprotein E–Deficient Mice Establishes Microvessels as Major Entry Pathways for Leukocytes to Advanced Lesions

¹

2011

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Background-There has been considerable speculation about the role of lesion microvessels in the accumulation of leukocytes in atherosclerosis. However, direct study of microvascular recruitment of leukocytes in lesions has not been performed, and the quantitative role for this route of entry is unclear. Methods and Results-Here, microvascular recruitment of leukocytes was studied in advanced lesions in 12-to 24-month-old apolipoprotein E-deficient (ApoE Ϫ/Ϫ ) mice. Histology and transmission electron microscopy demonstrated the presence of mainly adventitial, but also intimal, microvessels. Interactions between leukocytes and endothelium occurred in lesion venules. Leukocyte rolling was largely P-selectin dependent; however, residual rolling was mediated by L-selectin and endothelial P-selectin glycoprotein ligand 1. Leukocyte adhesion was significant and was attenuated in mice treated with antibodies against P-selectin, CD18, or both before preparation for intravital microscopy, suggesting acute activation of these 2 molecules by surgical trauma. Nonetheless, the density of firmly arrested leukocytes was 100-fold higher in lesion venules compared with the arterial lumen even in mice pretreated with antibodies against P-selectin and CD18, indicating strong recruitment of cells from venules that is unrelated to experimental manipulation. Fluorescent myelomonocytic cells in ApoE Ϫ/Ϫ mice carrying a knock-in mutation for enhanced green fluorescent protein (EGFP) in the lysozyme M locus (ApoE Ϫ/Ϫ /lysM EGFP/EGFP mice) were distributed specifically around lesion venules, but not around arterioles or capillaries, further indicating ongoing extravasation from venules into plaque tissue. Conclusions-These findings provide strong data for microvascular recruitment of leukocytes in atherosclerosis and indicate roles for L-selectin and P-selectin glycoprotein ligand 1 in this process. (Circulation. 2011;124:2129-2138.)

“…Although elevated wall shear stress in the upstream region is unlikely to directly induce mechanical rupture, the distinct shear stress conditions along atherosclerotic plaque can certainly result in a differential activation of biological processes, such as inflammatory mechanisms. For example, higher numbers of macrophages 8 and dendritic cells 9 were observed at the upstream plaque shoulder, which may indirectly contribute to plaque destabilization by activation of inflammatory pathways in this region. In contrast, higher numbers of smooth muscle cells (SMCs) were detected downstream, corresponding with the distal plaque growth.…”

mentioning

confidence: 99%

Carotid Plaque Vulnerability

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²

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³

et al. 2011

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Background and Purpose-Rupture of atherosclerotic plaques is one of the main causes of ischemic strokes. The aim of this study was to investigate carotid plaque vulnerability markers in relation to blood flow direction and the mechanisms leading to plaque rupture at the upstream side of carotid stenoses. Methods-Frequency and location of rupture, endothelial erosion, neovascularization, and hemorrhage were determined in longitudinal sections of 80 human carotid specimens. Plaques were immunohistochemically analyzed for markers of vulnerability. Plaque geometry was measured to reconstruct shape profiles of ruptured versus stable plaques and to perform computational fluid dynamics analyses. Results-In 86% of ruptured plaques, rupture was observed upstream. In this region, neovascularization and hemorrhage were increased, along with increased immunoreactivity of vascular endothelial and connective tissue growth factor, whereas endothelial erosion was more frequent downstream. Proteolytic enzymes, mast cell chymase and cathepsin L, and the proapoptotic protein Bax showed significantly higher expression upstream as compared with the downstream shoulder of atherosclerotic lesions. Comparison of geometric profiles for ruptured and stable plaques showed increased longitudinal asymmetry of fibrous cap and lipid core thickness in ruptured plaques. The specific geometry of plaques ruptured upstream induced increased levels of shear stress and increased pressure drop between the upstream and the downstream plaque shoulders. Conclusions-Vulnerability of the upstream plaque region is associated with enhanced neovascularization, hemorrhage, and cap thinning induced by proteolytic and proapoptotic mechanisms. These processes are reflected in structural plaque characteristics, analyses of which could improve the efficacy of vascular diagnostics and prevention.

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