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)

Small-diameter vascular grafts woven from bioresorbable lactide/glycolide copolymers have been successfully interposed into aortas of normal NZW rabbits. The current study examines the histologic and functional reactions to these bioresorbable grafts in severely hypercholesterolemic rabbits, a standard animal model of atherosclerosis. Sixty rabbits were placed on a 2% cholesterol, 6% peanut oil atherogenic diet. Baseline serum cholesterols and triglycerides were measured and repeated at operation 3 months later. Woven polyglactin 910 (PG910) grafts were interposed into infrarenal aortas. Fifty-two rabbits died on the diet or within 3 days of surgery and eight survived operation (normal NZW rabbit operative mortality is less than 10%). Cholesterol levels rose from 63 to 1989, p less than .001. Of the eight survivors, five died after 3 weeks, and one died after 2 1/2 months. Two were sacrificed at 2 and 4 months. Four aortic disruptions with retroperitoneal hematomas, one pseudoaneurysm, and one diffuse aneurysm were observed, greater than in normal rabbits, p less than .001. Inspection revealed severe atherosclerosis. Histologically, 3-week explants showed only small areas of neointima with myofibroblasts and endothelial cells; the outer capsules were infiltrated by lipid-laden macrophages. Graft material in 2- to 4-month explants was replaced by tissue with histologic atherosclerosis. More severe atherosclerosis was observed in native aortas at the perianastomotic areas than the more distant aortic segments. Abundant intracellular lipid was seen also in splenic histiocytes and hepatic cells with evidence of micronodular cirrhosis. Macrophages phagocytizing bioresorbable prostheses may release growth factors mediating the formation of a cellular tissue conduit. Severe hypercholesterolemia may alter monokine release from macrophages resulting in a weakened prosthesis/tissue complex.
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PMID:Effects of hypercholesterolemia on healing of vascular grafts. 191 76

Monocyte chemoattractant protein 1 (MCP-1) is a member of the chemokine family of cytokines that mediate leukocyte chemotaxis. The potent and specific activation of monocytes by MCP-1 may mediate the monocytic infiltration of tissues in atherosclerosis and other inflammatory diseases. We have isolated cDNAs that encode two MCP-1-specific receptors with alternatively spliced carboxyl tails. Expression of the receptors in Xenopus oocytes conferred robust mobilization of intracellular calcium in response to nanomolar concentrations of MCP-1 but not to related chemokines. The MCP-1 receptors are most closely related to the receptor for the chemokines macrophage inflammatory protein 1 alpha and RANTES (regulated on activation, normal T expressed and secreted). The identification of the MCP-1 receptor and cloning of two distinct isoforms provide powerful tools for understanding the specificity and signaling mechanisms of this important chemokine.
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PMID:Molecular cloning and functional expression of two monocyte chemoattractant protein 1 receptors reveals alternative splicing of the carboxyl-terminal tails. 814 86

Human vascular smooth muscle cells (VSMC) are a component of blood vessels, and secrete a variety of cytokines in atherosclerotic loci. Interleukin-11 (IL-11), a member of IL-6-like cytokines, is reported to be involved in inflammation and tissue remodeling, both of which are observed in atherosclerosis. However, no information is available as to the production of IL-11 by VSMC. Therefore, the expression of IL-11 in VSMC is investigated. The amounts of IL-11 protein and mRNA were determined by enzyme-linked immunosorbent assay (ELISA) and Northern blot analysis, respectively. The expression of IL-11 in VSMC was also immunohistochemically determined. IL-1 alpha, transforming growth factor-beta (TGF beta) and, to a lesser extent, tumor necrosis factor-alpha (TNF alpha) stimulated the IL-11 production by VSMC, and the stimulatory effects of IL-1 alpha and TGF beta on IL-11 production were dose-dependent. IL-1 alpha and TNF alpha synergistically augmented TGF beta-stimulated IL-11 production by VSMC. Immunohistochemical staining also revealed the expression of IL-11 protein in VSMC. Furthermore, IL-1 alpha, TGF beta, and TNF alpha induced IL-11 gene expression in VSMC. Because IL-6-like cytokines are reported to be cytoprotective, monokine-stimulated IL-11 may have a potent protective role in atherosclerotic lesions.
Atherosclerosis 1999 Jun
PMID:Monokine stimulation of interleukin-11 production by human vascular smooth muscle cells in vitro. 1040 98

Activated T lymphocytes accumulate early in atheroma formation and persist at sites of lesion growth and rupture, suggesting that they may play an important role in the pathogenesis of atherosclerosis. Moreover, atherosclerotic lesions contain the Th1-type cytokine IFN-gamma, a potentiator of atherosclerosis. The present study demonstrates the differential expression of the 3 IFN-gamma-inducible CXC chemokines--IFN-inducible protein 10 (IP-10), monokine induced by IFN-gamma (Mig), and IFN-inducible T-cell alpha chemoattractant (I-TAC)--by atheroma-associated cells, as well as the expression of their receptor, CXCR3, by all T lymphocytes within human atherosclerotic lesions in situ. Atheroma-associated endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages (MO) all expressed IP-10, whereas Mig and I-TAC were mainly expressed in ECs and MO, as detected by double immunofluorescence staining. ECs of microvessels within lesions also expressed abundant I-TAC. In vitro experiments supported these results and showed that IL-1beta, TNF-alpha, and CD40 ligand potentiated IP-10 expression from IFN-gamma-stimulated ECs. In addition, nitric oxide (NO) treatment decreased IFN-gamma induction of IP-10. Our findings suggest that the differential expression of IP-10, Mig, and I-TAC by atheroma-associated cells plays a role in the recruitment and retention of activated T lymphocytes observed within vascular wall lesions during atherogenesis.
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PMID:Differential expression of three T lymphocyte-activating CXC chemokines by human atheroma-associated cells. 1052 42

Chemokines or chemotactic cytokines represent an expanding family of structurally related small molecular weight proteins, recognised as being responsible for leukocyte trafficking and activation. Soon after the discovery of this class of cytokines, about a decade ago, monocyte chemoattractant protein-1 (MCP-1) was found to be highly expressed in human atherosclerotic lesions and postulated to be central in monocyte recruitment into the arterial wall and developing lesions. In this review, we will discuss our present knowledge about MCP-1 and its receptor CCR2 and their role in atherogenesis. Although less well established, other chemokines such as RANTES, MIP-1alpha and MIP-1beta have also been implicated in atherosclerotic lesion formation as are a number of more recently discovered chemokines like MCP-4, ELC and PARC. The role of these chemokines in the progression of atherosclerosis will be discussed as well as the emerging role of IL-8, mostly know for its effects on neutrophils. Particular attention will be given not only to the involvement of chemokines in the inflammatory recruitment of monocytes/macrophages, but also to their role in the related local immune responses and vascular remodelling which occur during the formation of unstable atherosclerotic plaques.
Atherosclerosis 1999 Dec
PMID:Chemokines and atherosclerosis. 1055 6

Atherosclerosis is an inflammatory disease. Platelet-endothelium interaction plays an important role in the pathophysiology of atherogenesis. We investigated the role of activated platelets for secretion of interleukin (IL)-1beta, monocyte chemotactic protein (MCP)-1 and macrophage inflammatory protein (MIP)-1alpha and expression of intercellular adhesion molecule (ICAM)-1 on endothelial cells. Human umbilical vein endothelial cells (HUVEC) were incubated with non-stimulated or ADP-activated platelets for 6 hr. Secretion of interleukin (IL)-1beta, MCP-1 and MIP-1alpha and surface expression of ICAM-1 were measured by ELISA and flow cytometry. In the presence of activated platelets, the secretion of IL-1beta, MCP-1, and MIP-1alpha and surface expression of ICAM-1 were significantly increased compared with non-activated platelets. The present study shows that activated platelets may contribute to expression of various inflammatory mediators on endothelial cells.
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PMID:Activated platelets induce secretion of interleukin-1beta, monocyte chemotactic protein-1, and macrophage inflammatory protein-1alpha and surface expression of intercellular adhesion molecule-1 on cultured endothelial cells. 1089 67

An auxiliary factor of mammalian multi-aminoacyl-tRNA synthetases, p43, is thought to be a precursor of endothelial monocyte-activating polypeptide II (EMAP II) that triggers proinflammation in leukocytes and macrophages. In the present work, however, we have shown that p43 itself is specifically secreted from intact mammalian cells, while EMAP II is released only when the cells are disrupted. Secretion of p43 was also observed when its expression was increased. These results suggest that p43 itself should be a real cytokine secreted by an active mechanism. To determine the cytokine activity and active domain of p43, we investigated tumor necrosis factor (TNF) and interleukin-8 (IL-8) production from human monocytic THP-1 cells treated with various p43 deletion mutants. The full length of p43 showed higher cytokine activity than EMAP II, further supporting p43 as the active cytokine. p43 was also shown to activate MAPKs and NFkappaB, and to induce cytokines and chemokines such as TNF, IL-8, MCP-1, MIP-1alpha, MIP-1beta, MIP-2alpha, IL-1beta, and RANTES. Interestingly, the high level of p43 was observed in the foam cells of atherosclerotic lesions. Therefore, p43 could be a novel mediator of atherosclerosis development as well as other inflammation-related diseases.
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PMID:A cofactor of tRNA synthetase, p43, is secreted to up-regulate proinflammatory genes. 1129 33

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

Chemokines are important mediators of leukocyte recruitment and activation that play critical roles in the pathology of inflammatory diseases such as atherosclerosis, rheumatoid arthritis and asthma. The vaccinia virus (strain Lister) expresses a 35 kDa soluble protein ('35K') that binds and inactivates a wide range of CC chemokines. We generated a recombinant adenovirus encoding soluble 35K (Ad35K). Ad35K-infected cell culture medium, containing recombinant 35K, potently reduced migration of CCR5-transfected 293 cells by 95% in response to the CC-chemokine RANTES, but had no effect on cells transfected with the CX3CR1 fractalkine receptor. Delivery of Ad35K to mice in vivo via tail vein injection resulted in expression of recombinant 35K in plasma and increased serum RANTES and MIP-1alpha levels when quantified by ELISA. However, chemotaxis of both CCR5-transfected cells and primary macrophages was inhibited by more than 90% by plasma from Ad35K-infected animals compared with control plasma from animals injected with AdGFP. Furthermore, 35K delivered by intra-peritoneal injection more than halved biogel-induced inflammatory cell recruitment in peritoneal exudates compared to AdGFP medium. These studies identify broad-spectrum CC-chemokine blockade using in vivo adenoviral-mediated recombinant 35K expression as a promising strategy to reduce local and systemic inflammation.
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PMID:Adenoviral-mediated delivery of a viral chemokine binding protein blocks CC-chemokine activity in vitro and in vivo. 1277 60

Blood platelets play critical roles in hemostasis, providing rapid essential protection against bleeding and catalyzing the important slower formation of stable blood clots via the coagulation cascade. They are also involved in protection from infection by phagocytosis of pathogens and by secreting chemokines that attract leukocytes. Platelet function usually is activated by primary agonists such as adenosine diphosphate (ADP), thrombin, and collagen, whereas secondary agonists like adrenalin do not induce aggregation on their own but become highly effective in the presence of low levels of primary agonists. Current research has revealed that chemokines represent an important additional class of agonists capable of causing significant activation of platelet function. Early work on platelet alpha-granule proteins suggested that platelet factor 4, now known as CXCL4, modulated aggregation and secretion induced by low agonist levels. Subsequent reports revealed the presence in platelets of messenger RNA for several additional chemokines and chemokine receptors. Three chemokines in particular, CXCL12 (SDF-1), CCL17 (TARC), and CCL22 (MDC), recently have been shown to be strong and rapid activators of platelet aggregation and adhesion after their binding to platelet CXCR4 or CCR4, when acting in combination with low levels of primary agonists. CXCL12 can be secreted by endothelial cells and is present in atherosclerotic plaques, whereas CCL17 and CCL22 are secreted by monocytes and macrophages. Platelet activation leads to the release of alpha-granule chemokines, including CCL3 (MIP-1alpha), CCL5 (RANTES), CCL7 (MCP-3), CCL17, CXCL1 (growth-regulated oncogene-alpha), CXCL5 (ENA-78), and CXCL8 (IL-8), which attract leukocytes and further activate other platelets. These findings help to provide a direct linkage between hemostasis, infection, and inflammation and the development of atherosclerosis.
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PMID:Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. 1285 50


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