Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Accumulation of cholesterol in the tunica intima of arteries is a feature of atherosclerotic development. Recently, the demonstration of oxidized LDL in atherosclerotic lesions considerably strengthened the possibility of its role in the atherogenesis in vivo. However, the mechanism of lipid accumulation in monocyte-derived macrophages has not yet been clarified. It has been reported that the complement system may be related to atherosclerosis. In this report, complement receptors in the atherosclerotic lesions obtained from autopsy sample were investigated. Initially C3b receptors were detected using sheep erythrocytes bearing human C3b (EAC1423b cells). EAC1423b cells adherent to only aortic sections showing intimal thickening, but not to intact artery. Second, immunostaining of consecutive aortic sections was performed. Apo B and C5b-9 complex were stained using the indirect immunoperoxidase method, and macrophage, C3b receptor (CR1) and C3bi receptor (CR3) were stained using monoclonal antibody in the alkaliphosphatase anti-alkaliphosphatase method. In the intact artery of 3 month old patient, antigen- specific staining were not observed. In intimal thickening and atheroma of older patients, consecutive sections suggested that complement receptor-expressing cells were macrophages. Staining for apo B antigen existed at extracellular site in the intima, and C5b-9 complex was observed in intima and partially in the media. The above data showed that macrophage complement receptors were expressed in the atherosclerotic lesions when the complement system was activated. We conclude that these data suggest that the complement system and complement receptors may be related to the uptake of LDL by macrophages.
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PMID:Complement receptors in atherosclerotic lesions. 153 10

The hallmark of early atherosclerosis is the accumulation of lipid-laden macrophages in the subendothelial space. Circulating monocytes are the precursors of these "foam cells," and recent evidence suggests that chemokines play important roles in directing monocyte migration from the blood to the vessel wall. Fractalkine (FK) is a structurally unusual chemokine that can act either as a soluble chemotactic factor or as a transmembrane-anchored adhesion receptor for circulating leukocytes. A polymorphism in the FK receptor, CX(3)CR1, has been linked to a decrease in the incidence of coronary artery disease. To determine whether FK is critically involved in atherogenesis, we deleted the gene for CX(3)CR1 and crossed these mice into the apoE(-/-) background. Here we report that FK is robustly expressed in lesional smooth muscle cells, but not macrophages, in apoE(-/-) mice on a high-fat diet. CX(3)CR1(-/-) mice have a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation. Taken together, these data provide strong evidence that FK plays a key role in atherogenesis.
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PMID:Decreased atherosclerosis in CX3CR1-/- mice reveals a role for fractalkine in atherogenesis. 1269 29

Expression of membrane-bound CX3CL1, a CX(3)C chemokine, can be strongly induced by inflammatory cytokines in primary endothelial cells, mediating capture and tight adhesion of cells, such as monocytes, that carry the CX(3)CR1 receptor. Here, we measured CX3CL1 mRNA and protein induction by human aortic smooth muscle cells (SMCs), another major component of vessel walls, in response to inflammatory stimuli, and analyzed the effect of membrane-bound CX3CL1 on monocyte adhesion, tissue factor (TF) expression, and tumor necrosis factor-alpha (TNF-alpha) released. In human vascular SMCs, CX3CL1 transcripts were induced after 4h of stimulation with a combination of TNF-alpha and interferon-gamma. Cell-associated and shedded CX3CL1 were measured with a specific ELISA, showing that only 30% of the protein was cleaved from the membrane. Expression of CX3CL1 by SMC increased adhesion of monocytic cells, an effect, which was blocked by soluble CX3CL1. Interestingly, monocyte adhesion to CX3CL1-coated plates partially inhibited lipopolysaccharide-induced TF expression and TNF-alpha release. Thus, CX3CL1, in addition to its adhesive/chemotactic functions, directly promotes monocyte antiinflammatory and antiprocoagulant responses. This could have important implications in clinical settings such as atherosclerosis, in which SMCs and monocytic cells are in close proximity.
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PMID:Fractalkine/CX3CL1 production by human aortic smooth muscle cells impairs monocyte procoagulant and inflammatory responses. 1282 4

Cigarette smoke and hemodynamic stress both contribute to vascular inflammation and associated atherosclerosis. We recently demonstrated direct activation of complement components C4 and C3 on human endothelial cells (EC). The present study was designed to explore complement activation on bone marrow microvascular endothelial cells (BMEC) and human umbilical vein endothelial cells (HUVEC) in response to endothelial cell injury by tobacco smoke extract, shear stress, or other known inflammatory and atherogenic mediators, lipopolysaccharide (LPS) and INF-gamma. Following treatment, confluent EC monolayers were exposed to plasma (60 min, 37 degrees C), and cell surface deposition of stable complement derivatives C4d, iC3b and SC5b-9 was measured in situ using an ELISA approach. Consistent with previous results, moderate levels of C4d, iC3b and SC5b-9 deposition were observed on native EC monolayers exposed to human plasma. Tobacco smoke and shear stress enhanced EC C4d deposition. In contrast, LPS and INF-gamma failed to affect EC mediated complement activation, despite evidence of EC activation illustrated by ICAM-1 expression. The combination of tobacco smoke and shear stress nearly doubled EC C4d expression. No increases in iC3b or SC5b-9 were noted, suggesting inhibition of classical and alternative pathway C3 convertase assembly or activity. Indeed, concomitantly increased surface expression of complement regulatory proteins CD35 (CR1) and CD55 was observed following EC exposure to tobacco smoke and shear stress. These results suggest that a balance between complement activation and regulation exists at the EC surface, and may impact vascular injury leading to thrombosis, arteriosclerosis, and atherogenesis.
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PMID:Regulated complement deposition on the surface of human endothelial cells: effect of tobacco smoke and shear stress. 1816 21

The fundamental importance of chemokines for atherogenesis, progression, and destabilization of atherosclerotic plaques is now widely appreciated, but the degree of complexity, specificity, and cooperativity harnessed by these signal molecules to govern atherogenic cell recruitment and homeostasis is still being refined. Since the role of chemokines in atherosclerotic vascular disease has been reviewed in this journal, significant progress has been accomplished in defining the regulation of chemokine expression and function in atherosclerosis. In this update, we will highlight these recent developments, in particular the identification of components regulating the transcriptional machinery of the proatherogenic chemokine CCL5, distinct roles of its receptors CCR1 and CCR5 in plaque formation and immunobalance, and differential site- and stage-specific effects of T cell-activating chemokines and their receptors, eg, CXCL10 and CXCR3. The contribution of the transmembrane chemokines CX(3)CL1 and CXCL16 with their respective receptors CX(3)CR1 and CXCR6 in the recruitment of T cell and monocyte subsets and shear-mediated plaque modulation will be discussed. Finally, the role of CXCR2 and CXCR4, their respective ligands CXCL1 and CXCL12, and the noncanonical dual agonist MIF in atheroprogression will be dissected. The considerable leap in insight over recent years leads us to anticipate further advances in comprehending the role of chemokines in atherosclerosis, allowing targeted interventions for its prevention and therapy.
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PMID:Chemokines in atherosclerosis: an update. 1856 99

CX(3)CR1 is a chemokine receptor with a single ligand, the membrane-tethered chemokine CX(3)CL1 (fractalkine). All blood monocytes express CX(3)CR1, but its levels differ between the main 2 subsets, with human CD16(+) and murine Gr1(low) monocytes being CX(3)CR1(hi). Here, we report that absence of either CX(3)CR1 or CX(3)CL1 results in a significant reduction of Gr1(low) blood monocyte levels under both steady-state and inflammatory conditions. Introduction of a Bcl2 transgene restored the wild-type phenotype, suggesting that the CX(3)C axis provides an essential survival signal. Supporting this notion, we show that CX(3)CL1 specifically rescues cultured human monocytes from induced cell death. Human CX(3)CR1 gene polymorphisms are risk factors for atherosclerosis and mice deficient for the CX(3)C receptor or ligand are relatively protected from atherosclerosis development. However, the mechanistic role of CX(3)CR1 in atherogenesis remains unclear. Here, we show that enforced survival of monocytes and plaque-resident phagocytes, including foam cells, restored atherogenesis in CX(3)CR1-deficent mice. The fact that CX(3)CL1-CX(3)CR1 interactions confer an essential survival signal, whose absence leads to increased death of monocytes and/or foam cells, might provide a mechanistic explanation for the role of the CX(3)C chemokine family in atherogenesis.
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PMID:CX3CR1 is required for monocyte homeostasis and atherogenesis by promoting cell survival. 1897 23

The chemokine and adhesion molecule fractalkine and its receptor CX(3)CR1 have emerged as interesting regulators in inflammation and related atherosclerosis. The pro-inflammatory status may be counteracted by appropriate treatment, such as in rehabilitation. We compared serum fractalkine concentrations of 46 patients with coronary heart disease (CHD) and 47 insulin-dependent diabetic patients (IDDM) following rehabilitation with those of 50 control subjects. Following rehabilitation serum fractalkine levels (477 + or - 225 pg/mL) in CHD patients were similar to those in control subjects (572 + or - 205 pg/mL; P = 0.303), whereas fractalkine levels were lower in IDDM patients (430 + or - 256 pg/mL; P = 0.042). No significant difference between CHD and IDDM patients was present (P = 0.319). Postprandial hyperlipemia may influence inflammation; thus, we investigated fractalkine levels four and eight hours after inducing postprandial hyperlipemia. However, we did not find any significant alterations in CHD and diabetic patients, whereas the fractalkine levels in controls were reduced. In vitro, lipofundin used as a hyperlipemic stimulus was added to vessel wall cells and reduced fractalkine levels. Low fractalkine levels in patients attending rehabilitation indicate a beneficial effect of the rehabilitation procedure on innate inflammatory pathways, such as the chemokine and adhesion molecule fractalkine.
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PMID:Patients with insulin-dependent diabetes or coronary heart disease following rehabilitation express serum fractalkine levels similar to those in healthy control subjects. 1985 23

Adipose tissue macrophages (ATMs) accumulate in fat during obesity and resemble foam cells in atherosclerotic lesions, suggesting that common mechanisms underlie both inflammatory conditions. CX(3)CR1 and its ligand fractalkine/CX(3)CL1 contribute to macrophage recruitment and inflammation in atherosclerosis, but their role in obesity-induced adipose tissue inflammation is unknown. Therefore, we tested the hypothesis that CX(3)CR1 regulates ATM trafficking to epididymal fat and contributes to the development of adipose tissue inflammation during diet-induced obesity. Cx(3)cl1 and Cx(3)cr1 expression was induced specifically in epididymal fat from mice fed a high-fat diet (HFD). CX(3)CR1 was detected on multiple myeloid cells within epididymal fat from obese mice. To test the requirement of CX(3)CR1 for ATM trafficking and obesity-induced inflammation, Cx(3)cr1(+/GFP) and Cx(3)cr1(GFP/GFP) mice were fed a HFD. Ly-6c(Low) monocytes were reduced in lean Cx(3)cr1(GFP/GFP) mice; however, HFD-induced monocytosis was comparable between strains. Total ATM content, the ratio of type 1 (CD11c(+)) to type 2 (CD206(+)) ATMs, expression of inflammatory markers, and T-cell content were similar in epididymal fat from obese Cx(3)cr1(+/GFP) and Cx(3)cr1(GFP/GFP) mice. Cx(3)cr1 deficiency did not prevent the development of obesity-induced insulin resistance or hepatic steatosis. In summary, our data indicate that CX(3)CR1 is not required for the recruitment or retention of ATMs in epididymal adipose tissue of mice with HFD-induced obesity even though CX(3)CR1 promotes foam cell formation. This highlights an important point of divergence between the mechanisms regulating monocyte trafficking to fat with obesity and those that contribute to foam cell formation in atherogenesis.
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PMID:CX3CR1 deficiency does not influence trafficking of adipose tissue macrophages in mice with diet-induced obesity. 2225 34

Chemokines play an important role in inducing chemotaxis of cells, piloting white blood cells in immune surveillance and are crucial parts in the development and progression of atherosclerosis. Platelets are mandatory players in the initiation of atherosclerotic lesion formation and are susceptible targets for and producers of chemokines. Several chemokine receptors on platelets have been described previously, amongst them CX(3)CR1, the receptor for fractalkine. The unique chemokine fractalkine (CX(3)CR1, FKN) exists as a soluble as well as a membrane-anchored glycoprotein. Its essential role in the formation of atherosclerotic lesions and atherosclerosis progression has been impressively described in mouse models. Moreover, fractalkine induces platelet activation and adhesion via a functional fractalkine receptor (CX(3)CR1) expressed on the platelet surface. Platelet activation via the FKN/CX(3)CR1-axis triggers leukocyte adhesion to activated endothelium, and fractalkine-induced platelet P-selectin is mandatory for leukocyte recruitment under arterial flow conditions. This review summarises the role of fractalkine as a potential local inflammatory mediator which influences platelet activation in the setting of atherosclerosis. Beyond that, aspects of a potential interaction between fractalkine and platelet responsiveness to antiplatelet drugs are described. Furthermore, the possible impact of high-density lipoprotein cholesterol (HDL-C) on atherosclerosis progression, platelet activation and fractalkine signalling are discussed.
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PMID:Fractalkine--a local inflammatory marker aggravating platelet activation at the vulnerable plaque. 2273 55

Monocyte/macrophages are implicated in initiation of angiogenesis, tissue/organ perfusion and atherosclerosis biology. We recently showed that chemokine receptor CX(3)CR1 is an essential regulator of monocyte/macrophage derived smooth muscle cell differentiation in the vessel wall after injury. Here we hypothesised the contribution of CX(3)CR1- CX(3)CL1 interaction to in vivo neovascularization and studied the functional consequences of genetic and pharmacologic targeting of CX(3)CR1 in formation, maturation and maintenance of microvascular integrity. Cells functionally deficient in CX(3)CR1 lacked matrix tunnelling and tubulation capacity in a 3D Matrigel assay. These morphogenic and cytokinetic responses were driven by CX(3)CL1-CX(3)CR1 interaction and totally abrogated by a Rho antagonist. To evaluate the role of CX(3)CR1 system in vivo, Matrigel plugs were implanted in competent CX(3)CR1(+/gfp) and functionally deficient CX(3)CR1(gfp/gfp) mice. Leaky microvessels (MV) were formed in the Matrigel implanted in CX(3)CR1(gfp/gfp) but not in CX(3)CR1(+/gfp) mice. In experimental plaque neovascularization immature MV phenotype was observed in CX(3)CR1(gfp/gfp) mice, lacking CX(3)CR1 positive smooth muscle-like cells, extracellular collagen and basement membrane (BM) laminin compared to competent CX(3)CR1(+/gfp) mice. This was associated with increased extravasation of platelets into the intima of CX(3)CR1(gfp/gfp) but not functionally competent CX(3)CR1 mice. Pharmacologic targeting using CX(3)CR1 receptor antagonist in wild type mice resulted in formation of plaque MV with poor BM coverage and a leaky phenotype. Our data indicate a hitherto unrecognised role for functional CX(3)CR1 in Matrigel and experimental plaque neovascularization in vivo, which may buttress MV collectively in favour of a more stable non-leaky phenotype.
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PMID:Role of CX3CR1 receptor in monocyte/macrophage driven neovascularization. 2343 46


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