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)

Chemokines are proinflammatory cytokines that function in leukocyte chemoattraction and activation and have recently been shown to block the HIV-1 infection of target cells through interactions with chemokine receptors. In addition to their function in viral disease, chemokines have been implicated in the pathogenesis of atherosclerosis. Expression of the CC chemokine monocyte chemoattractant protein-1 (MCP-1) is upregulated in human atherosclerotic plaques, in arteries of primates on a hypercholesterolaemic diet; and in vascular endothelial and smooth muscle cells exposed to minimally modified lipids. To determine whether MCP-1 is causally related to the development of atherosclerosis, we generated mice that lack CCR2, the receptor for MCP-1 (ref. 7), and crossed them with apolipoprotein (apo) E-null mice which develop severe atherosclerosis. Here we show that the selective absence of CCR2 decreases lesion formation markedly in apoE-/- mice but has no effect on plasma lipid or lipoprotein concentrations. These data reveal a role for MCP-1 in the development of early atherosclerotic lesions and suggest that upregulation of this chemokine by minimally oxidized lipids is an important link between hyperlipidaemia and fatty streak formation.
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PMID:Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. 973 72

Recruitment of blood monocytes into the arterial subendothelium is one of the earliest steps in atherogenesis. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine, is one likely signal involved in this process. To test MCP-1's role in atherogenesis, low density lipoprotein (LDL) receptor-deficient mice were made genetically deficient for MCP-1 and fed a high cholesterol diet. Despite having the same amount of total and fractionated serum cholesterol as LDL receptor-deficient mice with wild-type MCP-1 alleles, LDL receptor/MCP-1-deficient mice had 83% less lipid deposition throughout their aortas. Consistent with MCP-1 's monocyte chemoattractant properties, compound-deficient mice also had fewer macrophages in their aortic walls. Thus, MCP-1 plays a unique and crucial role in the initiation of atherosclerosis and may provide a new therapeutic target in this disorder.
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PMID:Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. 973 66

Local immune responses are thought to play an important role in the development of atherosclerosis. Histological studies have shown that human atherosclerotic lesions contain T lymphocytes throughout all stages of development, many of which are in an activated state. A number of novel CC chemokines have been described recently, which are potent chemoattractants for lymphocytes: PARC (pulmonary and activation-regulated chemokine), ELC (EBI1-ligand chemokine), LARC (liver and activation-regulated chemokine), and SLC (secondary lymphoid-tissue chemokine). Using reverse transcriptase-polymerase chain reaction and in situ hybridization, we have found gene expression for PARC and ELC but not for LARC or SLC in human atherosclerotic plaques. Immunohistochemical staining of serial plaque sections with specific cell markers revealed highly different expression patterns of PARC and ELC. PARC mRNA was restricted to CD68+ macrophages (n = 14 of 18), whereas ELC mRNA was widely expressed by macrophages and intimal smooth muscle cells (SMC) in nearly all of the lesions examined (n = 12 of 14). ELC mRNA was also found to be expressed in the medial SMC wall of highly calcified plaques (n = 4). Very low levels of ELC mRNA expression could also be detected in normal mammary arteries but no mRNA expression for PARC was detected in these vessels (n = 4). In vitro, ELC mRNA was found to be up-regulated in aortic SMC stimulated with tumor necrosis factor-a and interferon-gamma but not in SMC stimulated with serum. Both PARC and ELC mRNA were expressed by monocyte-derived macrophages but not monocytes. The expression patterns of PARC and ELC mRNA in human atherosclerotic lesions suggest a potential role for these two recently described CC chemokines in attracting T lymphocytes into atherosclerotic lesions.
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PMID:Expression and cellular localization of the CC chemokines PARC and ELC in human atherosclerotic plaques. 1002 95

Monocyte chemotactic protein-3 (MCP-3) is a CC chemokine that functions in chemoattraction and activation of monocytes, T lymphocytes, eosinophils, basophils, natural killer cells and dendritic cells. The activation of the target cells by MCP-3 is via specific chemokine receptors CCR2 and CCR3, of which CCR2 is shared with MCP-1. MCP-1 and CCR2 have been implicated in vascular diseases including atherosclerosis and restenosis, that are known to be involved in inflammation (accumulation of T lymphocytes and monocytes) and smooth muscle cell (SMC) activation (proliferation, migration and matrix deposition). To investigate a potential role of MCP-3 in vascular injury, the present work examined its mRNA expression in rat aortic SMCs stimulated with various inflammatory stimuli including LPS, TNF-alpha, IL-1beta, IFN-gamma and TGF-beta. A time- and concentration-dependant induction of MCP-3 mRNA in SMCs was observed by means of Northern analysis. A strikingly similar expression profile was observed for MCP-3 and MCP-1 mRNA in SMCs. Furthermore, MCP-3 mRNA expression was induced in rat carotid artery after balloon angioplasty. A significant induction in MCP-3 mRNA was observed in the carotid artery at 6 h (41-fold increase over control, P<0.001), 1 day (13-fold increase, P<0.001) and 3 days (6-fold increase, P<0.01) after balloon angioplasty as quantitated by reverse transcription and polymerase chain reaction. These data provide evidence for the cytokine-induced expression of MCP-3 in SMCs and in carotid artery after balloon angioplasty, suggesting a potential role of MCP-3 in the pathogenesis of restenosis and atherosclerosis.
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PMID:Expression of monocyte chemotactic protein-3 mRNA in rat vascular smooth muscle cells and in carotid artery after balloon angioplasty. 1056 16

Recent data suggest that angiotensin II AT1 receptor antagonists may be beneficial in the treatment of atherosclerosis. To clarify how AT1 receptor antagonists reduce atherosclerosis, the effect of irbesartan on atherosclerotic lesion development was determined in low-fat, chow-fed apolipoprotein (Apo) E-deficient mice. Irbesartan (50 mg/kg per day) strongly decreased lesion development after a 12-week treatment period (lesion size: irbesartan treated, 20,524 +/- 4,200 microm(2) vs. control, 99,600 +/- 14,500; 79.4% inhibition, p < 0.001). This effect was not due to an effect of irbesartan on lipoprotein levels because irbesartan slightly increased total cholesterol levels and decreased the ratio of Apo A-I relative to Apo B levels. Immunochemical analysis of the atherosclerotic lesions using the mac3 monoclonal antibody showed the presence of macrophages in the lesions of control mice, whereas sections from irbesartan-treated animals only showed occasional labeling in the lesion area. These data suggest that irbesartan inhibits monocyte/macrophage influx into the vessel wall. Therefore, expression levels of monocyte chemoattractant protein-1 (MCP-1), as well as other chemokines involved in macrophage infiltration into the lesion area, were measured in the aortic sinus of control and irbesartan-treated animals. Irbesartan treatment strongly decreased MCP-1 mRNA levels as well as MCP-1 immunostaining in the lesion area. This effect of irbesartan on MCP-1 occurred without an effect on CCR2, the receptor of MCP-1. Expression of macrophage inflammatory protein (MIP)-1alpha, another CC chemokine expressed in atherosclerotic lesions, was also reduced after irbesartan treatment, without effect on CCR3 and CCR5, the receptors of MIP-1alpha. Concomitantly, the expression of the angiogenic chemokines KC and MIP-2, which are functionally related to interleukin-8, were downregulated, whereas their shared receptor CXCR2 was upregulated. These data suggest that inhibition of the inflammatory component of lesion progression plays an important role in the inhibitory effect of AT1 receptor antagonists on atherosclerotic lesion formation.
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PMID:Angiotensin AT1 receptor antagonist irbesartan decreases lesion size, chemokine expression, and macrophage accumulation in apolipoprotein E-deficient mice. 1148 44

Macrophage inflammatory protein-related protein-2 (MRP-2) is a new member of the CC chemokine family that is recently identified in murine macrophages. MRP-2 is involved in leukocyte trafficking and activation, which can be implicated in inflammatory diseases including atherosclerosis. Little is known about the involvement of this novel chemokine MRP-2 in the pathogenesis of atherosclerosis. To explore the possible association of the MRP-2 with atherosclerosis, we investigated the effects of atherogenic diet on MRP-2 expression in mice. Male C57BL/6 mice were fed a high fat and cholesterol diet (20% fat and 1.5% cholesterol) or a control diet based on AIN-76 for 5, 10, or 14 weeks. The levels of total cholesterol, LDL cholesterol, and F2-isoprostanes in plasma were measured using appropriate enzymatic assays. Tumor necrosis factor alpha (TNF alpha) and MCP-1 release by peritoneal macrophages was determined by ELISA. The mRNA expression level of the MRP-2 was measured by RT-PCR. The levels of total cholesterol, LDL-cholesterol, and 8-iso-prostaglandin F2 alpha in plasma, well-known indexes of atherosclerosis, were significantly increased in the high fat and cholesterol diet group compared to those in the control. A significant increase in the TNF alpha and MCP-1 production by macrophages was also observed in the group fed high fat and cholesterol diet. The mRNA expression of MRP-2 was upregulated by oxLDL treatment in vitro and feeding a high fat and cholesterol diet in vivo at the late stage of atherosclerosis. These results suggest that MRP-2 may be an important contributing factor in the development of atherosclerosis.
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PMID:Alteration of a macrophages inflammatory protein-related protein-2 (MRP-2) response by high fat and cholesterol diet in mice. 1217 16

Chemokines and their receptors play regulatory roles in inflammatory reactions. Lipoprotein(a) is an atherogenic lipoprotein, however the mechanisms of its actions are not defined. Our interest in chemokines and their receptors was stimulated by the finding that incubation of Lp(a) with human umbilical vein endothelial cells produced a conditioned medium that was chemotactic for human monocytes. Since infiltration of monocytes into the vessel wall is an early lesion in atherosclerosis, this finding provided a novel mechanism to explain the relationship between Lp(a) and atherosclerosis. The chemoattractant produced by HUVEC was identified as CCL1/I-309, a CC chemokine previously reported to be secreted by stimulated monocytes/macrophages and T lymphocytes. CCR8, the CCL1 receptor, was identified on endothelial cells, and CCL1 was found to be a chemoattractant for these cells. Most recently we demonstrated functional CCR8 on human vascular smooth muscle cells and found that the Lp(a)-HUVEC conditioned medium is a chemoattractant for these cells. CCL1 increased metalloproteinase-2 production by HUVEC, an activity that enables these cells to remodel the vascular matrix. These studies suggest that CCR8 may play an important role in arterial wall pathology.
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PMID:Chemokine receptor-8: potential role in atherogenesis. 1248 97

Increasing evidence supports the involvement of inflammation in the early phases of atherogenesis. Recruitment of leukocytes within the vascular wall, controlled by chemokines, is an essential process in the development of this common disease. In this study, we report that blocking a chemokine pathway in vivo with the CC chemokine antagonist Met-RANTES reduces the progression of atherosclerosis in a hypercholesterolemic mouse model. The reduction of lesions was correlated with a diminution of expression of several major chemokines and chemokine receptors, a decrease in leukocyte infiltration, and an increase of collagen-rich atheroma, features associated with stable atheroma. Treatment was well tolerated and serum lipid profiles were not affected. Whereas genetically engineered mice with deletion of either a CC chemokine or its receptor have demonstrated resistance to disease, to our knowledge, this is the first demonstration that treatment with a chemokine receptor antagonist limits the progression of atherosclerosis in vivo. Thus, our findings indicate that blockade of chemokine receptor/ligand interactions might become a novel therapeutic strategy to reduce the evolution of this common disease.
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PMID:Antagonism of RANTES receptors reduces atherosclerotic plaque formation in mice. 1465 31

Atherosclerosis is a chronic inflammatory disease that involves the recruitment of leukocytes to the arterial wall. Leukotactin-1 (Lkn-1), a new member of the CC chemokine family, is a potent chemoattractant for leukocytes and thus is implicated in inflammatory diseases. In this study, we investigated the possible association of Lkn-1 with human atherosclerosis. Atherosclerotic lesion and plasma samples were obtained from atherosclerotic patients. Human THP-1 monocyte-derived foam cells were prepared by treatment with an oxidized low-density lipoprotein. The expression level of Lkn-1 or its receptors mRNA was measured by RT-PCR analysis. Levels of plasma Lkn-1, MCP-1, ICAM-1 and total cholesterol were measured by ELISA or enzymatic assay. Lkn-1 expression was markedly enhanced not only at the mRNA level in human atherosclerotic lesions, but also at the circulating level in atherosclerosis patients compared with normal subjects. An in vitro study revealed that the level of Lkn-1 release was significantly enhanced by oxidative stress or proatherogenic mediators in macrophages and macrophage-derived foam cells. Lkn-1 stimulated endothelial cells to release ICAM-1, which is implicated in atherogenesis. Taken together, our data suggest that Lkn-1 plays an important role in the development of atherosclerosis.
Atherosclerosis 2004 May
PMID:Involvement of leukotactin-1, a novel CC chemokine, in human atherosclerosis. 1513 48

The CC chemokine, monocyte chemoattractant protein-1 (MCP-1), plays a crucial role in the initiation of atherosclerosis and has direct effects that promote angiogenesis. To develop a specific inhibitor for MCP-1-induced angiogenesis, we performed in vitro selection employing phage display random peptide libraries. Most of the selected peptides were found to be homologous to the second extracellular loops of CCR2 and CCR3. We synthesized the peptide encoding the homologous sequences of the receptors and tested its effect on the MCP-1 induced angiogenesis. Surface plasmon resonance measurements demonstrated specific binding of the peptide to MCP-1 but not to the other homologous protein, MCP-3. Flow cytometry revealed that the peptide inhibited the MCP-1 binding to THP-1 monocytes. Moreover, CAM and rat aortic ring assays showed that the peptide inhibited MCP-1 induced angiogenesis. Our observations indicate that the MCP-1-binding peptide exerts its anti-angiogenic effect by interfering with the interaction between MCP-1 and its receptor.
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PMID:Inhibition of the angiogenesis by the MCP-1 (monocyte chemoattractant protein-1) binding peptide. 1575 47


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