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)

Endothelin-1 (ET-1) enhances the biosynthesis of interleukin-6 (IL-6) in endothelial cells and bone marrow-derived stromal cells of the rat. This study investigates (i) whether ET-1 stimulates the formation of tumour necrosis factor alpha (TNF alpha) or interferon-gamma (IFN gamma) in cultured macrophages or in the anaesthetized rat. Incubation of J774.2 macrophages with ET-1 (0.001-1 microM) caused a concentration- and time-dependent increase in the concentration of TNF alpha, but not of IFN gamma, in the culture medium. The increase in TNF alpha caused by stimulation of J774.2 macrophages was abolished by pretreatment of cells with (i) the protein synthesis inhibitor cycloheximide, (ii) with the selective ETA-receptor antagonists BQ-123 or BQ-485 (but not the selective ETB-receptor antagonist BQ-788), (iii) the tyrosine kinase inhibitors genistein or tyrphostin AG126, or (iv) with the glucocorticoid, dexamethasone. The inhibition by dexamethasone of the formation of TNF alpha by cells activated with ET-1 is not due to the formation of lipocortin-1 (LC1), as it was not reduced by a monoclonal antibody against LC1. Systemic administration (i.v.) of ET-1 (1 nmol.kg-1) to anaesthetized rats caused a rapid and sustained (maximum: 45 min; return to baseline: within 180 min) rise in the plasma levels of TNF alpha. This is the first demonstration that ET-1 can release proinflammatory cytokines in vitro and in vivo. The generation of TNF alpha caused by ET-1 involves (in sequence) the (i) activation of ETA-receptors, (ii) activation of tyrosine kinase resulting in the phosphorylation of intracellular proteins, (iii) the activation of, hitherto, unknown transcription factors, finally resulting in (iv) transcription and translation of the TNF alpha gene. The generation of TNF alpha by cells activated with ET-1 points to a pro-inflammatory role of ET-1 in diseases associated with local (e.g. atherosclerosis, heart failure) or systemic inflammation (circulatory shock), which are associated with high ET-1 plasma levels.
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PMID:Endothelin-1 stimulates the biosynthesis of tumour necrosis factor in macrophages: ET-receptors, signal transduction and inhibition by dexamethasone. 944 16

Increased plasma levels of homocysteine are an independent risk factor for atherothrombosis. While the endothelial cytotoxicity of homocysteine has been attributed to oxidative stress associated with the reactivity of the thiol group, the oxidative effect of homocysteine on vascular smooth-muscle cells has not been investigated. Recent evidence suggests that expression of inducible nitric oxide synthase (iNOS), or Nos2 gene product, in vascular smooth-muscle cells may, in part, promote atherosclerosis by increasing local oxidative stress. We therefore hypothesized that homocysteine contributes to atherosclerosis by affecting cytokine-induced production of nitric oxide (NO) by vascular smooth-muscle cells. Confluent rat aortic smooth-muscle cells were exposed to a range of concentrations of homocysteine for 4 hr, then were treated with interferon-gamma, interleukin-1 beta, and lipopolysaccharide to induce iNOS. Media NOx content (nitrite plus S-nitrosothiol) was measured over 24 hr using the Saville reaction. As compared to controls, 5, 50, and 500 microM homocysteine produced a dose-dependent increase in media NOx content, an effect that was primarily a consequence of increased S-nitrosothiol production. iNOS enzyme activity and iNOS protein levels were increased significantly in the homocysteine-treated cells as compared with controls. Northern analysis showed that homocysteine treatment increased steady-state Nos2 mRNA levels by 61% at 6 hr as compared with controls, an effect that was not caused by changes in message stability. By electrophoretic mobility shift assay, homocysteine activated NF-kappa B and also potentiated cytokine activation of NF-kappa B. These data demonstrate that exposure of vascular smooth-muscle cells to pathophysiologically relevant concentrations of homocysteine prior to cytokine stimulation leads both to an increase in NO production and to an NF-kappa B-mediated increase in Nos2 transcription. Upregulation of Nos2 may contribute to the inflammatory response that characterizes early atherogenesis and may, in part, account for the adverse vascular effects of hyperhomocysteinemia.
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PMID:Homocysteine-induced nitric oxide production in vascular smooth-muscle cells by NF-kappa B-dependent transcriptional activation of Nos2. 946 80

Intimal thickening caused by accumulation of cells, lipids, and connective tissue characterizes atherosclerosis, an arterial disease that leads to cardiac and cerebral infarction. Apoptosis, or genetically programmed cell death, is important for the development and morphogenesis of organs and tissues. As in other tissues, cells of cardiovascular tissues can undergo apoptosis. Increased apoptosis has been found in both human and animal atherosclerotic lesions, mediating tissue turnover and lesion development. In addition to vascular cells, many activated immune cells, mainly macrophages and T cells, are present in atherosclerotic lesions, where these cells produce biologically active substances such as the proinflammatory cytokines tumor necrosis factor, interleukin-1 (IL-1), and interferon-gamma. Simultaneous exposure to these cytokines may trigger apoptosis of vascular smooth muscle cells. The products of death-regulating genes including Fas/Fas ligand, members of IL-1 beta cysteinyl protease (caspase) family, the tumor suppressive gene p53, and the protooncogene c-myc have been found in vascular cells and may participate in the regulation of vascular apoptosis during the development of atherosclerosis. Abnormal occurrence of apoptosis may take place in atherosclerotic lesions, including attenuation or acceleration of the apoptotic death process. The former may cause an increase in the cellularity of the lesions, and the latter can reduce cellular components important for maintaining the integrity and stability of the plaques. Clarification of the molecular mechanism that regulates apoptosis may help design a new strategy for treatment of patients with atherosclerosis and its major complications, heart attack and stroke.
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PMID:Regulation of programmed cell death or apoptosis in atherosclerosis. 947 49

Recent evidence has shown that apoptotic cells are present in human atherosclerotic lesions. However, the molecular mechanism of the induction of apoptosis in atherosclerotic lesions is not clear. Since T cells are present in almost all stages of atherosclerosis, we examined whether T cells can modulate the expression of Fas, a death signal, in endothelial cells (ECs), using a coculture system. Human umbilical vein ECs were cultured alone or cocultured with human peripheral T cells activated with phorbol myristate acetate and ionomycin. Flow cytometric (FACscan) analysis showed that Fas antigen was up-regulated in ECs when ECs were cocultured for 24 h with activated T cells. However, Fas antigen was not up-regulated in ECs cocultured with non-activated T cells. The up-regulation of Fas antigen induced by coculturing ECs with activated T cells was partially, but significantly, neutralized by antibody against interferon-gamma (IFN-gamma). Actually, incubation with IFN-gamma induced a dose-dependent increase in the level of Fas antigen in ECs cultured alone. These findings indicate that activated T cells induce up-regulation of Fas antigen in ECs. Thus, the Fas system induced by activated T cells could participate in the mechanism of EC injury in atherosclerotic lesions.
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PMID:Activated T cells induce up-regulation of Fas antigen in cultured endothelial cells. 947 50

Emerging evidence is redefining traditional concepts of coronary atherosclerosis. Recent data indicate that severe stenoses, the traditional focus of attention, do not cause most coronary events. Rather, interest has increased in the often less stenotic but more vulnerable lesions that are characterized by thin fibrous caps, large lipid accumulations, large numbers of macrophages, and depletion of smooth muscle cells. Such lesions appear prone to rupture, which allows the blood to come into contact with the highly thrombogenic material in the lipid core of the plaque, thereby precipitating thrombosis. The fibrous cap may become weakened through decreased synthesis of the extracellular matrix or increased degradation of the matrix. The cytokine interferon-gamma, produced by T-lymphocytes, inhibits the ability of smooth muscle cells to synthesize collagen, a structurally important component of the fibrous cap. A family of enzymes known as matrix metalloproteinases can degrade all major constituents of the vascular extracellular matrix: collagen, elastin, and proteoglycans. Additional studies on the biochemical mechanisms of atherosclerosis may provide a fuller understanding of the ways in which lipid-lowering therapy can confer clinical benefit.
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PMID:Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization. 955 May 2

beta-chemokines play an important role in the development of immunologic reactions. Macrophages are major beta-chemokine-producing cells during T-cell directed, delayed-type hypersensitivity reactions in tissues, and have been reported to be important producers of beta-chemokines in the lymph nodes of HIV-1-infected individuals. However, the physiological signals responsible for inducing macrophages to produce beta-chemokines have not been established. Two soluble T cell products, interferon-gamma and granulocyte-macrophage colony stimulating factor, were added to cultured macrophages, but failed to stimulate the production of macrophage inflammatory protein-1alpha and -1beta; regulated upon activation, normal T cell expressed and secreted (RANTES); or monocyte chemoattractant protein-1. Instead, direct cell-cell contact between macrophages and cells engineered to express CD40L (also known as CD154) resulted in the production of large amounts of macrophage inflammatory protein-1alpha and -1beta, and RANTES (all ligands for CCR5), and monocyte chemoattractant protein-1 (a ligand for CCR2). Supernatants from CD40L-stimulated macrophages protected CD4(+) T cells from infection by a nonsyncytium-inducing strain of HIV-1 (which uses CCR5 as a coreceptor). These results have implications for granulomatous diseases, and conditions such as atherosclerosis and multiple sclerosis, where CD40L-bearing cells have been found in the macrophage-rich lesions where beta-chemokines are being produced. Overall, these findings define a pathway linking the specific recognition of antigen by T cells to the production of beta-chemokines by macrophages. This pathway may play a role in anti-HIV-1 immunity and the development of immunologic reactions or lesions.
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PMID:CD40 ligand (CD154) stimulation of macrophages to produce HIV-1-suppressive beta-chemokines. 956 Feb 54

Atherosclerosis is associated with immune activation. T cells and macrophages infiltrate atherosclerotic plaques and disease progression is associated with formation of autoantibodies to oxidized lipoproteins. In the apo E knockout mouse, a genetic model of cholesterol-induced atherosclerosis, congenital deficiency of macrophages, lymphocytes, or interferon-gamma receptors result in reduced lesion formation. We have now evaluated whether immune modulation in the adult animal affects disease development. Injections of 7-wk-old male apo E knockout mice with polyclonal immunoglobulin preparations (ivIg) during a 5-d period reduced fatty streak formation over a 2-mo period on cholesterol diet by 35%. Fibrofatty lesions induced by diet treatment for 4 mo were reduced by 50% in mice receiving ivIg after 2 mo on the diet. ivIg treatment also reduced IgM antibodies to oxidized LDL and led to inactivation of spleen and lymph node T cells. These data indicate that ivIg inhibits atherosclerosis, that it is effective both during the fatty streak and plaque phases, and that it may act by modulating T cell activity and/or antibody production. Therefore, immunomodulation may be an effective way to prevent and/or treat atherosclerosis.
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PMID:Immunoglobulin treatment reduces atherosclerosis in apo E knockout mice. 972 59

Thrombosis on the substrate of a disrupted plaque causes most acute coronary events. The physical integrity of the plaque thus governs the most important clinical manifestations of atherosclerosis. Of particular importance is the extracellular matrix of the fibrous capsule overlying the thrombogenic core of the atheroma. Stable atheroma generally have thick fibrous caps, and smaller lipid cores than lesions that have ruptured. Accumulating evidence supports a key role for inflammation as another critical determinant of the stability of human atherosclerotic plaques. Plaques that rupture usually have more abundant leucocytic infiltrates than those considered stable. Inflammatory mediators such as cytokines can influence several biological processes that regulate the stability of the plaque's fibrous cap, and thus its resistance to rupture. For example, interferon-gamma produced by activated T lymphocytes within atheroma inhibits the production of interstitial forms of collagen by human vascular smooth muscle cells. Inflammatory cytokines such as interleukin-1, tumour necrosis factor (TNF) and CD-40 ligand (a cell surface homologue of TNFalpha) can also elicit the expression by macrophages and smooth muscle cells of proteolytic enzymes that can weaken the extracellular matrix. We have hypothesised that lipid lowering reduces stimuli for the inflammatory response within the complex atherosclerotic lesion. Recent studies in rabbits with experimentally produced atherosclerosis have indeed shown that lipid lowering can (i) reduce macrophage numbers, (ii) decrease expression of the collagenolytic enzyme MMP-1, and (iii) reinforce the plaque's fibrous skeleton by increasing the content of interstitial collagen. By reducing local inflammation, lipid lowering can thus stabilise the plaque's fibrous cap, rendering the atheroma less prone to rupture and to precipitate thrombotic complications. These observations provide a mechanistic basis for understanding the marked reduction in acute coronary events and cerebrovascular accidents observed in patients treated with agents that reduce plasma lipids.
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PMID:New insights into plaque stabilisation by lipid lowering. 974 May 36

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

Stromelysin-3 is an unusual matrix metalloproteinase, being released in the active rather than zymogen form and having a distinct substrate specificity, targeting serine proteinase inhibitors (serpins), which regulate cellular functions involved in atherosclerosis. We report here that human atherosclerotic plaques (n = 7) express stromelysin-3 in situ, whereas fatty streaks (n = 5) and normal arterial specimens (n = 5) contain little or no stromelysin-3. Stromelysin-3 mRNA and protein colocalized with endothelial cells, smooth muscle cells, and macrophages within the lesion. In vitro, usual inducers of matrix metalloproteinases such as interleukin-1, interferon-gamma, or tumor necrosis factor alpha did not augment stromelysin-3 in vascular wall cells. However, T cell-derived as well as recombinant CD40 ligand (CD40L, CD154), an inflammatory mediator recently localized in atheroma, induced de novo synthesis of stromelysin-3. In addition, stromelysin-3 mRNA and protein colocalized with CD40L and CD40 within atheroma. In accordance with the in situ and in vitro data obtained with human material, interruption of the CD40-CD40L signaling pathway in low density lipoprotein receptor-deficient hyperlipidemic mice substantially decreased expression of the enzyme within atherosclerotic plaques. These observations establish the expression of the unusual matrix metalloproteinase stromelysin-3 in human atherosclerotic lesions and implicate CD40-CD40L signaling in its regulation, thus providing a possible new pathway that triggers complications within atherosclerotic lesions.
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PMID:Expression of stromelysin-3 in atherosclerotic lesions: regulation via CD40-CD40 ligand signaling in vitro and in vivo. 1004 48


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