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)

The role of various inflammatory mechanisms and oxidative stress in the development of atherosclerosis and arterial hypertension (AH) has been increasingly acknowledged during recent years. Hypertension per se or factors that cause hypertension along with other complications lead to infiltration of activated leukocytes in the vascular wall, where these cells contribute to the development of vascular injury by releasing cytokines, oxygen radicals, and other toxic mediators. However, molecular mechanisms underlying leukocyte activation at transcriptional level in AH are still far from being clear. To solve this problem we employed cDNA microarray technology to reveal the differences in gene expression in peripheral blood leukocytes from patients with AH compared with healthy individuals. The microarray data were verified by a semi-quantitative RT-PCR method. We found 25 genes with differential expression in leukocytes from AH patients among which 21 genes were upregulated and 4 genes were downregulated. These genes are implicated in apoptosis (CASP2, CASP4, and CASP8, p53, UBID4, NAT1, and Fte-1), inflammatory response (CAGC, CXCR4, and CX3CR1), control of MAP kinase function (PYST1, PAC1, RAF1, and RAFB1), vesicular trafficking of molecules among cellular organelles (GDI-1 and GDI-2), cell redox homeostasis (GLRX), cellular stress (HSPA8 and HSP40), and other processes. Gene expression pattern of the majority of genes was similar in AH patients independent of the disease stage and used hypotensive therapy, but was clearly different from that of normotensive subjects.
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PMID:Altered gene expression pattern in peripheral blood leukocytes from patients with arterial hypertension. 1734 25

Recent genetic evidence has implicated the adhesive chemokine CX3CL1 and its leukocyte receptor CX3CR1 in atherosclerosis. We previously proposed a mechanism involving foam cell anchorage to vascular smooth muscle cells because: 1) CX3CL1 and CX3CR1 are expressed by both cell types in mouse and human atherosclerotic lesions; 2) foam cells are reduced in lesions in cx3cr1(-/-)apoE(-/-) mice; and 3) proatherogenic lipids (oxidized low density lipoprotein [oxLDL] and oxidized linoleic acid derivatives) induce adhesion of primary human macrophages to primary human coronary artery smooth muscle cells (CASMCs) in vitro in a macrophage CX3CR1-dependent manner. Here we analyze this concept further by testing whether atherogenic lipids regulate expression and function of CX3CL1 and CX3CR1 on CASMCs. We found that both oxLDL and oxidized linoleic acid derivatives indirectly up-regulated CASMC CX3CL1 at both the protein and mRNA levels through an autocrine feedback loop involving tumor necrosis factor alpha production and NF-kappaB signaling. Oxidized lipids also up-regulated CASMC CX3CR1 but through a different mechanism. Oxidized lipid stimulation also increased adhesion of macrophages to CASMCs when CASMCs were stimulated prior to assay, and a synergistic pro-adhesive effect was observed when both cell types were prestimulated. Selective inhibition with a CX3CL1-specific blocking antibody indicated that adhesion was strongly CASMC CX3CL1-dependent. These findings support the hypothesis that CX3CR1 and CX3CL1 mediate heterotypic anchorage of foam cells to CASMCs in the context of atherosclerosis and suggest that this chemokine/chemokine receptor pair may be considered as a pro-inflammatory target for therapeutic intervention in atherosclerotic cardiovascular disease.
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PMID:Atherogenic lipids induce adhesion of human coronary artery smooth muscle cells to macrophages by up-regulating chemokine CX3CL1 on smooth muscle cells in a TNFalpha-NFkappaB-dependent manner. 1745 71

Within the chemokine family of small chemotactic polypeptides CX3CL1 (fractalkine) and CXCL16 (SR-PSOX) are exceptional in that they are synthesized as transmembrane molecules and can be cleaved from the cell surface to produce a soluble chemoattractant. As transmembrane molecules on the surface of endothelial cells, CX3CL1 and CXCL16 can interact with their receptors CX3CR1 and CXCR6, respectively, which are expressed on leukocyte subtypes. This interaction leads to cell-cell adhesion that is resistant to shear forces. Transmembrane CX3CL1 and CXCL16 are constitutively shed from the cell surface by the activity of a disintegrin and metalloproteinase (ADAM) 10, and cleavage can be rapidly enhanced by activation of the closely related enzyme ADAM17. This cleavage leads to the downregulation of adhesive properties and may even result in the detachment of bound cells. Functionally, both chemokines appear to exert homeostatic and inflammatory activities. Basal expression of CX3CL1 or CXCL16 may be relevant for positioning and survival of tissue-homing leukocytes. Upregulated expression is found under inflammatory conditions such as atherosclerosis where CXCL16 may have a dual function by acting as an adhesion molecule and by promoting uptake of oxidized LDL as a scavenger receptor. Accumulating evidence from knockout mice and genetic polymorphisms in humans points towards a differential contribution of CX3CL1 and CXCL16 in atherosclerosis, where shedding may serve to further regulate their biological functions. Small molecules that block either the receptors or the shedding enzymes of transmembrane chemokines need to be tested in animal models of vascular inflammation.
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PMID:Transmembrane chemokines: versatile 'special agents' in vascular inflammation. 1747 79

Fractalkine/CX3CR1 pathway is considered a major modulator of atherosclerosis. In the present study, expression of CX3CR1 on PBMCs/monocytes of healthy individuals and coronary artery diseased patients was initially assessed by flow cytometry. Effects of pre-inflammatory cytokines interferon (INF)-gamma and tumor necrosis factor (TNF)-alpha on expression of CX3CR1 and a single representative of each major chemokine family (CCR5 and CXCR4) were further assessed in three cell models: THP-1 monocytes, Jurkat T lymphocytes and primary monocytes isolated from healthy donors. Finally, effects of angiotensin-converting enzyme (ACE) inhibitors captopril, lisinopril and angiotensin receptor blocker (ARB) losartan on chemokine receptor expression were evaluated in the same cell models either in a naive or stimulated state. INF-gamma significantly affected the chemokine receptor phenotype of THP-1 cells by increasing the rate of CX3CR1-positive cells. Pre-treatment with the ACE inhibitors, captopril and lisinopril, and the ARB, losartan, did not influence these effects. Captopril and lisinopril similarly had no effect on either stimulated or naive primary monocytes. Yet, a small but repeatable increase in CX3CR1 expression after treatment with losartan was noted. Nevertheless, the latter observation did not retain statistical significance after applying the Bonferroni correction. In conclusion, our data did not indicate any significant effect of the ACE inhibitors on the chemokine receptor phenotype of monocytes.
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PMID:CX3CR1 receptor is up-regulated in monocytes of coronary artery diseased patients: impact of pre-inflammatory stimuli and renin-angiotensin system modulators. 1752 10

Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis. Fractalkine, a CX3C/chemokine (CX3CL1), mediates monocytes-macrophage infiltration in activated endothelium, suggesting its specific role in atherosclerosis-related inflammation. In this study, we evaluate the following in early RA patients: the expression of fractalkine receptor (CX3CR1) on CD4+/CD28- T cells, a subset involved in atherosclerotic infiltration; the correlation between this subset and validated markers of early atherosclerosis. CD4+ T cells were isolated by immunomagnetics beads in 50 early RA patients and 26 healthy controls (HC). After isolation, CD4+/CD28-/CX3CR1+ T lymphocytes were assessed by FACS analysis. Endothelial dysfunction was evaluated by both carotid intima-media thickness (IMT) and flow-mediated vasodilation (FMV). We observed: a higher expansion of CD4+/CD28- subset in RA patients when compared to HC (7.7%, 5.15-9.7 vs. 0.7%, 0.2-1.5, P < 0.01; respectively); this expansion directly correlated with increased IMT (0.91 mm, 0.5-1.3 vs. 0.7 mm, 0.2-1, P < 0.01; RA vs. C, respectively) and inversely correlated with FMV (3.5%, 1.7-7 vs. 9%, 3.5-11, P < 0.01; RA vs. C, respectively); the large majority of CD4+/CD28-, in RA, coexpressed CX3CR1 (93%, 67-99 vs. 30%, 10-48, P < 0.01; RA vs. C, respectively); this expansion significantly correlated with both the parameters of premature vascular damage and DAS 28. Our data suggest that CX3CL1/CX3CR1 axis might play a role in the induction and development of the endothelial dysfunction during RA.
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PMID:Surface expression of fractalkine receptor (CX3CR1) on CD4+/CD28 T cells in RA patients and correlation with atherosclerotic damage. 1780 30

Fractalkine (FKN) is a membrane-bound chemokine that can be released by proteolysis to produce soluble FKN (s-FKN). FKN and its receptor, CX3CR1, are believed to be important factors in atherosclerosis and may play a role in acute inflammatory responses. Although FKN is expressed on endothelial cells (ECs), CX3CR1 is reported to reside mainly on certain leukocyte populations. RT-PCR and Western blotting demonstrated that both human coronary artery and umbilical vein ECs expressed CX3CR1 mRNA and protein. Confocal microscopy showed that CX3CR1 was located at the cell membrane and to a lesser extent in the cytoplasm. Following exposure of both types of ECs to hypoxia and reoxygenation, FKN expression increased rapidly and s-FKN was shed into the culture medium. The addition of s-FKN protein to cultured ECs resulted in a dose-dependent increase in intercellular adhesion molecule (ICAM)-1 mRNA. Perfusion of mouse hearts with s-FKN protein increased expression of ICAM-1 protein in vascular endothelium. Transfection of ECs with CX3CR1-interfering RNA to knockdown the receptor resulted in decreased ICAM-1 expression after s-FKN stimulation. In addition, when ECs were stimulated with s-FKN, greater adhesion of human neutrophils to the ECs was observed. This increase was ICAM-1 dependent and was blocked by CX3CR1 knockdown. Following exposure to s-FKN, ECs exhibited increased phosphorylation of Jak2 and Stat5 and the ICAM-1 expression induced by s-FKN was blocked by silencing of Stat5 with small interfering RNA. Vascular ECs express both FKN and its receptor CX3CR1. s-FKN is shed from ECs following hypoxia/reoxygenation and acts through CX3CR1 on ECs to increase ICAM-1 expression and promote neutrophil adhesion through activation of the Jak-Stat5 pathway.
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PMID:Fractalkine upregulates intercellular adhesion molecule-1 in endothelial cells through CX3CR1 and the Jak Stat5 pathway. 1788 15

Chemokines are mainly involved in the recruitment of leukocytes into tissues, a key feature of inflammation. Through its unique receptor CX3CR1, the chemokine CX3CL1 participates in diverse inflammatory processes including arterial atherosclerosis and cerebral or renal inflammation. Using a phage display strategy, we engineered a hCX3CL1 analog (named F1) with a modified N terminus. F1 bound specifically to cells expressing hCX3CR1 and had a K(d) value close to that of native CX3CL1. F1 was not a signaling molecule and did not induce chemotaxis, calcium flux, or CX3CR1 internalization. However, it potently inhibited the CX3CL1-induced calcium flux and chemotaxis in CX3CR1-expressing primary cells of human and murine origin with an IC(50) of 5-50 nM. It also efficiently inhibited the cell adhesion mediated by the CX3CL1-CX3CR1 axis. Finally, in a noninfectious murine model of peritonitis, F1 strongly inhibited macrophage accumulation. These data reveal a prototype molecule that is the first bona fide antagonist of hCX3CR1. This molecule could be used as a lead compound for the development of a novel class of anti-inflammatory substances that act by inhibiting CX3CR1.
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PMID:An engineered CX3CR1 antagonist endowed with anti-inflammatory activity. 1957 Dec 53

Monocytes are central mediators in the advance of atherosclerotic plaque, making them a natural therapeutic target for reducing disease burden. Here, we highlight recent advances in our current understanding of monocyte heterogeneity and its relevance to regulation of monocyte accumulation and function within atherosclerotic plaques. Differences that distinguish monocyte subsets include differential expression of chemokine receptors, especially CCR2 and CX3CR1. Ablation of expression of these 2 receptors (or their ligands) in mice has an additive inhibition on monocyte recruitment to atherosclerotic plaques. Moreover, simultaneously interfering with 3 key pathways--CCR2, CX3CR1, and CCR5--essentially abolishes atherosclerosis in mice. Here, we discuss how these chemokine receptors act at multiple points on at least 1 monocyte subset, regulating their mobilization from bone marrow, survival, or recruitment to plaques. Finally, we discuss how this knowledge may be useful clinically, emphasizing that CX3CR1 may in particular be a viable target for therapeutic manipulation of monocyte-derived cell fate in cardiovascular disease.
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PMID:Regulation of the migration and survival of monocyte subsets by chemokine receptors and its relevance to atherosclerosis. 1975 73

The clinical presentation of systemic vasculitis can vary widely and include skin disorders, neuropathy, eye symptoms, and systemic inflammation. The precise molecular mechanisms underlying this syndrome are not fully understood, but the importance of a chronic imbalance of the cytokines and chemokines involved in orchestrating inflammatory responses is now recognized. In similar fashion, atherosclerosis is now recognized to be a chronic inflammatory disease in which chemokines play important roles. In the current review, we discuss the involvement of CX3CL1, which is a unique member of the chemokine family, and its receptor, CX3CR1, in the pathogenesis of these vasculopathies.
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PMID:Relevance of the CX3CL1/fractalkine-CX3CR1 pathway in vasculitis and vasculopathy. 2000 58

To investigate the possible association between V249I and T280M polymorphisms and carotid atherosclerosis (CAS) in a Han population in northern China we studied 328 patients with increased carotid artery intima-media thickness (C-IMT) and 292 healthy controls with normal C-IMT. T280M and V249I polymorphic genotypes of CX3CR1 were determined by polymerase chain reaction restriction fragment length polymorphism. Results showed that the M280 allele frequency in CAS group was significantly lower than that in the controls. Logistic regression analysis revealed that the decreased frequency of the M280 allele was an independent risk factor for CAS.
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PMID:Relationship between CX3CR1 genetic polymorphism and carotid atherosclerosis. 2004 17


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