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 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

The chemokine receptor CX3CR1 is a proinflammatory leukocyte receptor specific for the chemokine fractalkine (FKN or CX3CL1). In two retrospective studies, CX3CR1 has been implicated in the pathogenesis of atherosclerotic cardiovascular disease (CVD) based on statistical association of a common receptor variant named CX3CR1-M280 with lower prevalence of atherosclerosis, coronary endothelial dysfunction, and acute coronary syndromes. However, the general significance of CX3CR1-M280 and its putative mechanism of action have not previously been defined. Here we show that FKN-dependent cell-cell adhesion under conditions of physiologic shear is severely reduced in cells expressing CX3CR1-M280. This was associated with marked reduction in the kinetics of FKN binding as well as reduced FKN-induced chemotaxis of primary leukocytes from donors homozygous for CX3CR1-M280. We also show that CX3CR1-M280 is independently associated with a lower risk of CVD (adjusted odds ratio, 0.60, P = 0.008) in the Offspring Cohort of the Framingham Heart Study, a long-term prospective study of the risks and natural history of this disease. These data provide mechanism-based and consistent epidemiologic evidence that CX3CR1 may be involved in the pathogenesis of CVD in humans, possibly by supporting leukocyte entry into the coronary artery wall. Moreover, they suggest that CX3CR1-M280 is a genetic risk factor for CVD.
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PMID:Chemokine receptor mutant CX3CR1-M280 has impaired adhesive function and correlates with protection from cardiovascular disease in humans. 1269 29

Chemokines released by the endothelium have proaggregatory properties on platelets. Fractalkine, a recently discovered membrane-bound chemokine with a transmembrane domain, is expressed in vascular injury; however, the effects of fractalkine on platelets have not yet been investigated. Blood was taken from healthy Wistar-Kyoto rats and the expression of the fractalkine receptor on platelets was demonstrated. The modulation of surface expression of P-selectin was assessed by flow cytometry. P-selectin expression was significantly enhanced by in vitro stimulation with recombinant rat fractalkine compared with baseline levels. Selectively inhibiting the function of recombinant fractalkine by an antagonizing antibody or the disruption of the G-protein-coupled intracellular signaling cascade of the fractalkine receptor by pertussis toxin (PTX) completely prevented fractalkine-mediated platelet activation. Preincubation with apyrase significantly attenuated the fractalkine-induced degranulation. In a flow chamber model of platelet adhesion, stimulation with fractalkine significantly enhanced platelet adhesion to collagen and fibrinogen. Similar to P-selectin expression, enhanced adhesion could be prevented by the antagonizing antibody or preincubation of platelets with PTX. Fractalkine, which is overexpressed in atherosclerosis and vascular injury, contributes to platelet activation and adhesion and hence is likely to play a pathophysiologically important role for increased thrombogenesis in vascular diseases.
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PMID:Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion. 1296 73

Fractalkine (now also called CX3CL1) is a unique chemokine that functions not only as a chemoattractant but also as an adhesion molecule and is expressed on endothelial cells activated by proinflammatory cytokines, such as interferon-gamma and tumor necrosis factor-alpha. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes, including natural killer (NK) cells and cytotoxic T lymphocytes, which contain high levels of intracellular perforin and granzyme B, and on macrophages. Soluble fractalkine causes migration of NK cells, cytotoxic T lymphocytes, and macrophages, whereas the membrane-bound form captures and enhances the subsequent migration of these cells in response to secondary stimulation with other chemokines. Furthermore, stimulation through membrane-bound fractalkine activates NK cells, leading to increased cytotoxicity and interferon-gamma production. Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of various clinical disease states or processes, such as atherosclerosis, glomerulonephritis, cardiac allograft rejection, and rheumatoid arthritis. In addition, polymorphisms in CX3CR1, which reduce its binding activity to fractalkine, have been reported to increase the risk of HIV disease and to reduce the risk of coronary artery disease. This review will examine new concepts underlying fractalkine-mediated leukocyte migration and tissue damage, focusing primarily on the pathophysiological roles of fractalkine in various clinical conditions, especially in atherosclerosis and vascular injury.
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PMID:Fractalkine in vascular biology: from basic research to clinical disease. 1296 92

Fractalkine is an unusual tumor necrosis factor (TNF)-alpha-induced chemokine. The molecule is tethered to cells that express it and produces strong and direct adhesion to leukocytes expressing fractalkine receptor. However, the potential mechanism and significance of TNF-alpha-induced fractalkine expression in vascular endothelial cells are poorly understood. Here we show that in primary cultured endothelial cells TNF-alpha-induced fractalkine mRNA expression is mediated mainly through phosphatidylinositol 3'-kinase activation and nuclear factor (NF)-kappaB mediated transcriptional activation, along with GC-rich DNA-binding protein-mediated transcription. Interestingly, GC-rich DNA-binding protein inhibitors, mithramycin A and chromomycin A3, strongly suppressed TNF-alpha-induced fractalkine mRNA expression, possibly through inhibition of transcriptional activities by NF-kappaB and Sp1. In fact, direct inhibition of NF-kappaB and Sp1 bindings by decoy oligonucleotides suppressed TNF-alpha-induced fractalkine expression. Histologically, TNF-alpha-induced fractalkine expression was observed markedly in arterial and capillary endothelial cells, endocardium, and endothelium of intestinal villi, and slightly in venous endothelial cells, but not at all in lymphatic endothelial cells of intestine. Mithramycin A markedly suppressed TNF-alpha-induced fractalkine expression in vivo. These results indicate that TNF-alpha-stimulated fractalkine expression could act as part of arterial endothelial adhesion to leukocytes and monocytes during inflammation and atherosclerosis. NF-kappaB and Sp1 inhibitors such as mithramycin A may provide a pharmacological approach to suppressing these processes.
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PMID:Tumor necrosis factor-alpha induces fractalkine expression preferentially in arterial endothelial cells and mithramycin A suppresses TNF-alpha-induced fractalkine expression. 1511 13

Fractalkine (CX3CL1) is of particular interest in atherogenesis because it can serve as an adhesion molecule and a chemokine. Fractalkine and its receptor CX3CR1 are expressed in atherosclerotic lesions of humans and mice. However, the effect of fractalkine deficiency on atherosclerosis susceptibility is unknown. Fractalkine-deficient mice on the C57BL/6 (B6) background were bred to the atherosclerosis-sensitizing B6.ApoE(-/-) and B6.LDLR(-/-) backgrounds. Compared with controls, aortic-root lesion area was unchanged in fractalkine-deficient male and female B6.ApoE(-/-) mice at 16 weeks of age and males at 12 weeks of age, but it was mildly reduced (30%, P = 0.005) in females at 12 weeks of age. In contrast, lesion area at the brachiocephalic artery (BCA) was reduced dramatically by approximately 85% in fractalkine-deficient females [42,251 +/- 26,136 microm(2) (n = 15) vs. 6,538 +/- 11,320 microm(2);(n = 24), P < 0.0001] and males [36,911 +/- 32,504 microm(2) (n = 24) vs. 6,768 +/- 8,595 microm(2) (n = 14); P = 0.001] at 16 weeks of age. Fractalkine-deficient B6.ApoE(-/-) mice were comparable with controls in body weight, plasma cholesterol, plasma high-density lipoprotein cholesterol and white blood cell counts. On the B6.LDLR(-/-) background, lesion areas were reduced by 35% at the aortic root (P < 0.01) and by 50% at the BCA (P < 0.05) in fractalkine-deficient females at 16 weeks of age. Lesions in fractalkine-deficient mice on the B6.ApoE(-/-) and B6.LDLR(-/-) backgrounds were less complex and contained significantly fewer macrophages than controls. In conclusion, the major reduction of atherosclerosis in fractalkine-deficient mice appears to be at the BCA rather than the aortic root.
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PMID:Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. 1559 19

The migration of leukocytes into inflamed peripheral tissues and lymphoid organs involves a cascade of molecular events finely regulated by cell adhesion molecules and chemokines. Fractalkine/CX3CL1 is a membrane-bound chemokine that functions not only as a chemoattractant but also as an adhesion molecule, and is expressed on endothelial cells activated by proinflammatory cytokines. The fractalkine receptor, CX3CR1, is expressed on cytotoxic effector lymphocytes including NK cells and cytotoxic effector T cells (T(CE)), mature monocytes/macrophages, and mucosal dendritic cells, all of which play important roles in elimination of pathogens and cancer cells. Recently, accumulating evidence in both clinical studies and animal disease models has shown that fractalkine is also involved in the pathogenesis of various chronic inflammatory diseases, such as rheumatoid arthritis and atherosclerosis. This article reviews the unique functions of fractalkine and its pathophysiological roles in various clinical conditions.
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PMID:[Fractalkine and inflammatory diseases]. 1599 76

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


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