Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

15-Lipoxygenase (15-LO) catalyzes hydroperoxidation of fatty acids, a reaction of potential relevance to inflammation, membrane remodeling, and atherosclerosis. In human leukocytes, 15-lipoxygenation of arachidonic acid produces 15-(S)-hydroxyeicosatetraenoic acid and lipoxin A4, which suppress white cell chemotaxis, adherence, and activation, and antagonize proinflammatory leukotrienes. Interleukin (IL)-13, produced by T-helper subset 2 (TH-2) lymphocytes, specifically and potently induced 15-LO gene expression and enzyme activity in human monocytes. Among other TH-2 lymphokines, this induction of 15-LO is shared by IL-4 but not by IL-10. Interferon-gamma, a product of TH-1 lymphocytes, blocked IL-13-mediated induction of 15-LO. The induction of the anti-inflammatory 15-LO pathway by IL-13 reveals a new facet of IL-13 biology that supports its role as a cytokine with potential to down-regulate inflammatory pathways. The contrasting effects of interferon-gamma and IL-13 on 15-LO induction demonstrate mechanisms by which T-lymphocyte subsets may modulate macrophage/monocyte function in inflammation or atherosclerosis.
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PMID:Induction of 15-lipoxygenase by interleukin-13 in human blood monocytes. 796 80

We have investigated the requirement for c-myc downregulation in the growth arrest of vascular smooth muscle cells (VSMCs). Rat VSMCs were infected with a retrovirus vector directing constitutive expression of either the complete human c-Myc protein (VSM-myc cells) or the c-Myc deletion mutant D106-143, which is inactive in cotransformation and autosuppression assays (VSM-D106-143 myc cells). Clones of transfected VSM-myc cells were isolated that constitutively expressed a range of levels of c-Myc protein from that observed in normal proliferating VSMCs to approximately seven times normal. The growth rates of these clones and their responses to growth inhibitors were then assessed. VSM-myc clones possessed a shorter mean intermitotic time than normal cells, which was inversely correlated (P < .05) with the level of c-Myc protein expressed. VSM-myc cells also expressed lower levels of alpha-smooth muscle actin mRNA and protein and exhibited an altered morphology. The proliferation of normal VSMCs and VSM-D106-143 myc cells was inhibited by serum reduction (0.5% fetal calf serum) and also by treatment with interferon-gamma (100 IU/mL), heparin (50 micrograms/mL), 8-bromo-cAMP (0.1 mmol/L), or 8-bromo-cGMP (0.1 mmol/L). In contrast, proliferation of VSM-myc cells was not inhibited by any of these agents, even if present at 10-fold higher concentrations. However, approximately 75% of VSM-myc cells expressing levels of c-Myc protein seen in normal proliferating VSMCs underwent apoptosis after 4 days of serum reduction or treatment with interferon-gamma. The results show that constitutive c-myc expression induces continuous cell proliferation, reduction in alpha-smooth muscle actin expression and apoptosis in VSMCs. We conclude that downregulation of c-myc is a prerequisite for growth arrest and subsequent survival of VSMCs. Conversely, deregulated c-myc expression may be important in the proliferation and death of VSMCs--characteristics of the pathogenesis of atherosclerosis.
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PMID:Deregulated expression of the c-myc oncogene abolishes inhibition of proliferation of rat vascular smooth muscle cells by serum reduction, interferon-gamma, heparin, and cyclic nucleotide analogues and induces apoptosis. 811 60

Recent observations have demonstrated the presence of activated T lymphocytes and macrophages in human atherosclerotic lesions. Cells found within these lesions produce cytokines that alter vascular homeostasis in a manner that promotes atherogenesis. To elucidate the role of these immunocompetent cells in human atherosclerosis, the localization of various cytokines with an analysis of immunophenotypic features of the cellular infiltrates was studied in normal aortas from children; and in later phases of the disease (including fatty streaks and fibrous or atheromatous plaques). Semi-quantitative analysis of cytokine-expressing cells was also investigated with serial sectioning. In 4 of 9 young subjects, the grossly normal aorta contained relatively cell-rich areas which were located preferentially around the ostia of intercostal arteries and were composed of isolated or layered T lymphocytes and macrophages. In these prelesional areas, interleukin-1 (IL-1), IL-2 receptor (IL-2R) and tumour necrosis factor (TNF) were detected in the cytoplasm of the infiltrating cells, whereas no detectable reactivity was noted for IL-2, IL-6, interferon-gamma (IFN-gamma) or lymphotoxin (LT). In fatty streaks and full-grown atheromas including "cap" and "shoulder" regions, various numbers of T lymphocytes, macrophages and macrophage foam cells were present. In these lesion areas, especially where the cellular infiltrates were numerous, macrophage foam cells and smooth muscle cells expressed not only IL-1 and TNF but also IL-6. The ratio of IL-2R positive cells showed a tendency to decrease with advance of the disease process. Electron-microscopic examination of lesion areas demonstrated ultrastructural aspects of the cognate cell-to-cell interaction, as shown by the direct apposition of lymphocytes to macrophages or macrophage foam cells. These results suggest that a specific in situ, cell mediated hypersensitivity plays a pivotal role in the nascent as well as the progression stages of human atherosclerosis.
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PMID:Localization of T lymphocytes and macrophages expressing IL-1, IL-2 receptor, IL-6 and TNF in human aortic intima. Role of cell-mediated immunity in human atherogenesis. 829 Dec 16

An association between cytomegalovirus infection, cardiac allograft rejection, and atherosclerosis has been described. It has been suggested that cytomegalovirus induces major histocompatibility complex antigen expression in the graft and may trigger rejection. The induction of major histocompatibility complex antigens is thought to be mediated by interferon-gamma produced by activated T cells during the infection. To study whether cytomegalovirus infection induces major histocompatibility complex class II antigen expression in heart endothelium, cultured rat heart endothelial cells were infected with rat cytomegalovirus. The infection was shown by cytopathic effect and immunofluorescence using monoclonal cytomegalovirus-specific antibodies. Major histocompatibility complex class II antigen expression was analyzed before and during cytomegalovirus infection by two different methods, by a fluorescence-activated cell sorter and immunoperoxidase techniques using monoclonal antibodies. Uninfected endothelial cell cultures were treated with interferon-gamma and used as positive controls of class II induction. Induction of class II antigens was recorded in cytomegalovirus-infected endothelial cell cultures, and during the course of infection the class II expression increased toward the appearance of cytopathic effect. In uninfected cells, class II was induced by interferon-gamma, but this induction could be inhibited by adding antiinterferon-gamma antibody to the cultures. However, anti-interferon-gamma did not inhibit the induction of class II caused by cytomegalovirus. In conclusion, cytomegalovirus induced major histocompatibility complex class II antigen expression in rat heart endothelial cells in vitro. This induction of class II was independent of interferon-gamma and was caused by the virus itself. Direct induction of class II antigens by cytomegalovirus in heart endothelium may also be involved in rejection mechanisms in vivo.
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PMID:Cytomegalovirus induces class II expression in rat heart endothelial cells. 803 20

Smooth muscle cells (SMC) are the major cell type found in the walls of large blood vessels and appear to participate in local immune and inflammatory reactions, as well as in certain vascular diseases. We tested whether human arterial SMC can produce in vitro the colony stimulating factors (CSFs), granulocyte macrophage-CSF (GM-CSF) and macrophage CSF (M-CSF). Untreated internal mammary artery and aortic SMC produced no detectable GM-CSF but constitutively made M-CSF, measured by ELISA and radioimmunoassay, respectively. Interleukin-1 (IL-1) and, to a lesser extent, tumor necrosis factor alpha (TNF alpha) stimulated GM-CSF formation within 3 h; mRNA levels also increased particularly in the presence of the protein synthesis inhibitor, cycloheximide. IL-1, TNF alpha and, in addition, interferon-gamma (IFN-gamma) raised the M-CSF levels within 6 h; cycloheximide potentiated the effects of IL-1 and TNF alpha on mRNA levels. These results suggest that cytokine-stimulated human arterial SMC may be a source of the M-CSF found in atherosclerotic lesions. Since monocytes/macrophages can be activated by GM-CSF and M-CSF, while GM-CSF can also affect granulocyte function, SMC may participate in inflammatory reactions and vascular diseases by releasing these cytokines.
Atherosclerosis 1993 Mar
PMID:Cytokine regulation of granulocyte-macrophage colony stimulating factor and macrophage colony-stimulating factor production in human arterial smooth muscle cells. 850 51

Interferon-inducible protein-10 (IP-10) is a member of the C-X-C chemokine family. Using mRNA differential display, we isolated a rat homologue to murine and human IP-10 from lipopolysaccharide-stimulated carotid arteries. Our studies demonstrated that IP-10 is a potent mitogenic and chemotactic factor for vascular smooth muscle cells, the critical features of smooth muscle cells for their contribution to the pathogenesis of atherosclerosis and restenosis. IP-10 induced a concentration-dependent stimulation of DNA synthesis, cell proliferation, and cell migration of rat aortic smooth muscle cells. A concentration- and time-dependent IP-10 mRNA induction was observed in lipopolysaccharide- or interferon-gamma-stimulated, but not interleukin-1beta- or tumor necrosis factor-alpha-stimulated smooth muscle cells. A marked synergistic effect on IP-10 mRNA expression was observed when smooth muscle cells were challenged with interferon-gamma together with interleukin-1beta or tumor necrosis factor-alpha. Furthermore, IP-10 mRNA expression was induced in the rat carotid artery after balloon angioplasty. The mitogenic and chemotactic features of IP-10 for smooth muscle cells, along with its discrete induction in cultured vascular smooth muscle cells and in carotid arteries after balloon angioplasty (neointima formation) suggest that IP-10 may play an active and distinct role in vascular remodeling processes.
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PMID:Interferon-inducible protein-10 involves vascular smooth muscle cell migration, proliferation, and inflammatory response. 879 75

The intercellular adhesion molecule (ICAM) 1 is an Ig-like cell adhesion molecule expressed by several cell types, including leukocytes and endothelial cells. It can be induced in a cell-specific manner by several cytokines, for example, tumor necrosis factor-alpha, interleukin-1, and interferon-gamma, and inhibited by glucocorticoids. Its ligands are the membrane-bound integrin receptors LFA-1 and Mac-1 on leukocytes, CD43, the soluble molecule fibrinogen, the matrix factor hyaluronan, rhinoviruses, and Plasmodium falciparum malaria-infected erythrocytes. ICAM-1 expression is predominantly transcriptionally regulated. The ICAM-1 promoter contains several enhancer elements, among them a novel kappa B element which mediates effects of 12-O-tetradecanoylphorbol-13-acetate, interleukin-1, lipopolysaccharide, tumor necrosis factor-alpha, and glucocorticoids. Expression regulation is cell specific and depends on the availability of cytokine/hormone receptors, signal transduction pathways, transcription factors, and posttranscriptional modification. ICAM-1 plays a role in inflammatory processes and in the T-cell mediated host defense system. It functions as a costimulatory molecule on antigen-presenting cells to activate MHC class II restricted T-cells, and on other cell types in association with MHC class I to activate cytotoxic T-cells. ICAM-1 on endothelium plays an important role in migration of (activated) leukocytes to sites of inflammation. ICAM-1 is shed by the cell and detected in plasma as sICAM-1. Regulation and significance of sICAM-1 are as yet unclear, but sICAM-1 is increased in many pathological conditions. ICAM-1 may play a pathogenetic role in rhinovirus infections. Derangement of ICAM-1 expression probably contributes to the clinical manifestations of a variety of diseases, predominantly by interfering with normal immune function. Among these are malignancies (e.g., melanoma and lymphomas), many inflammatory disorders (e.g., asthma and autoimmune disorders), atherosclerosis, ischemia, certain neurological disorders, and allogeneic organ transplantation. Interference with ICAM-1 leukocyte interaction using mAbs, soluble ICAM-1, antisense ICAM-1 RNA, and in the case of melanoma mAb-coupled immunotoxin, may offer therapeutic possibilities in the future. Integration of knowledge concerning membrane-bound and soluble ICAM-1 into a single functional system is likely to contribute to elucidating the immunoregulatory function of ICAM-1 and its pathophysiological significance in various disease entities.
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PMID:Intercellular adhesion molecule-1. 883 67

Oxidized low-density lipoprotein (LDL) is currently regarded as a tentative key player in atherosclerosis by virtue of its ability to induce intracellular lipid accumulation and to modulate cell functions in the vessel wall. We previously demonstrated that inducible nitric oxide (NO) synthase activity is attenuated in lipid-laden J774 macrophages obtained by incubation with oxidized LDL 200 micrograms ml-1 for 24 h. In the present study we investigated the effect of oxidized LDL in a lower concentration (20 micrograms ml-1) or for a shorter time (6 h) and the possible mediator role of prostaglandin E2 and prostacyclin. Prostaglandins and the NO synthase metabolites citrulline and nitrite were elevated in the 24 h supernatant after immune stimulation with interferon-gamma 100 U ml-1 with or without lipopolysaccharide 10 micrograms ml-1. Pretreatment with oxidized LDL 20 micrograms ml-1 for 18 h decreased nitrite release by 31 +/- 2%, whereas prostaglandin production was not affected. A 6 h pre-exposure to 200 micrograms ml-1 had an opposite effect: it significantly potentiated interferon-gamma-stimulated prostaglandin E2 (10-fold), prostacyclin (7-fold), nitrite (1.5-fold), and citrulline (2.4-fold) release. Indomethacin 10 microM abolished the prostaglandin production and largely prevented the oxidized LDL-dependent increase in NO synthase activity. Acetylated LDL was without effect. The data show that the immune-induced release of NO is potentiated or suppressed, depending on the conditions of exposure to oxidized LDL. The potentiation due to short, high-dose exposure is partly mediated by prostaglandins since indomethacin inhibited both processes.
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PMID:Dual effects of oxidized low-density lipoprotein on immune-stimulated nitric oxide and prostaglandin release in macrophages. 886 25

We recently reported that tumor necrosis factor alpha is able to cause a dose-dependent and persistent reduction in gap junctional intercellular communication between primary human smooth muscle cells. In order to study whether this observed persistent reduction in gap junctional intercellular communication is a unique feature for tumor necrosis factor alpha, the present study focuses on the effects of other growth factors and cytokines on gap junctional intercellular communication. Platelet-derived growth factor AA and BB (PDGF-AA, PDGF-BB), basic fibroblast growth factor (bFGF), interleukin-6 and interferon-gamma were able to modulate gap junctional intercellular communication between primary human smooth muscle cells in vitro. However, our results demonstrate that the magnitude and nature of the observed effects are growth factor- and cytokine-specific. PDGF-AA, PDGF-BB and interleukin-6 caused a transient reduction in gap junctional intercellular communication, while bFGF induced a transient increase in gap junctional intercellular communication. Interferon-gamma was shown to be capable of causing a persistent reduction in gap junctional intercellular communication. In addition, PDGF-AA, PDGF-BB, bFGF, interleukin-6, interferon-gamma and tumor necrosis factor alpha all stimulated smooth muscle cell proliferation. These observations suggest a more complex relationship between modulation of gap junctional intercellular communication and cell proliferation than current hypotheses imply. The implications of the observed effects of growth factors and cytokines on gap junctional intercellular communication between smooth muscle cells in relation to the process of atherosclerosis is discussed.
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PMID:Modulation of intercellular communication between smooth muscle cells by growth factors and cytokines. 888 70

The demonstration of lipid loaded macrophages in atherosclerotic tissue has led to the development of in vitro systems to elucidate the mechanisms involved in lipid accumulation. Here we have characterised the changes which occur in human monocyte-derived macrophage (MDM) lipids during culture in either human serum (HS) or foetal calf serum (FCS). MDM cultured in HS were rapidly converted to lipid filled foam cells, as assessed using HPLC analysis and oil red-O staining and compared with the same cells grown in FCS. However, the lipids which accumulated were predominantly triglycerides with smaller amounts of unesterified cholesterol (UC) and only traces of cholesteryl esters (CE). alpha-Tocopherol (alpha-TocH) was present at higher levels in MDM cultured in HS compared to the same cells grown in FCS. MDM lipid accumulation was dependent on the triglyceride-rich lipoprotein (TGRL) fraction of human serum; accordingly, supplementation of FCS with human TGRL also induced MDM lipid accumulation. The relationships between cellular lipid accumulation and secretion of apolipoprotein E (apo E) and lipoprotein lipase (LPL) as well as expression of the low density lipoprotein receptor-related protein (LRP) were also examined. MDM lipid accumulation was associated with increased apo E secretion but did not alter extracellular LPL activity. The lipid accumulation which was induced by HS was potently inhibited (but not reserved) by the inflammatory cytokine interferon-gamma (IFN gamma), and this was associated with decreased apo E production, LPL secretion and expression of LRP. These studies reveal striking differences in the lipid composition of MDM cultured in either HS or FCS, and indicate that oil red-O staining is not necessarily associated with cholesteryl ester accumulation in human macrophages. Furthermore, the effect that serum-induced lipid accumulation has on the specific MDM functions studied should be appreciated when developing in vitro macrophage models.
Atherosclerosis 1997 Jan 03
PMID:Regulation of serum-induced lipid accumulation in human monocyte-derived macrophages by interferon-gamma. Correlations with apolipoprotein E production, lipoprotein lipase activity and LDL receptor-related protein expression. 905 Nov 97


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