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)

A comparative study of leukocyte adhesion to the endothelium of the thoracic aorta and left carotid artery in rats has been performed after administration of two hyperlipidemic diets for 15 days, proinflammatory agents (thrombin, lipopolysaccharide and zymosan activated serum) and plasma expanders [dextran, polyvinylpyrrolidone (PVP), rat albumin and several bovine albumins from different sources]. Leukocytes adhered to the endothelium were demonstrated in surface preparations by esterase activity. Activation of circulating leukocytes was measured by nitroblue tetrazolium reduction and luminol enhanced chemiluminescence. Both hyperlipidemic diets produced, in all rats, more leukocyte adhesion in the aorta than in the carotid artery. All proinflammatory agents produced at 1 h, increases in leukocyte adhesion--which in all rats were greater in the carotid artery than in the aorta--and leukocyte activation, which was higher at 3 h than at 1 h. Dextran, PVP, bovine albumins 103700 and A-4503 at 18 h produced slight increases in leukocyte adhesion in the aorta but not in the carotid artery. Rat albumin and bovine albumin A-7906 determined an intense leukocyte adhesion at 18 h which was not preferential to either vessel. Adhesion produced by A-7906 was maximal at 12 h and partially inhibited by dexamethasone. This last albumin produced leukocyte activation at 3 h and was sequestered 5 min after administration, reaching normal values at 1 h. Albumins 103700 and A-4503 neither activated leukocytes nor were sequestered after administration.
Atherosclerosis 1994 Oct
PMID:Effect of hyperlipidemic diets, proinflammatory agents and plasma expanders on leukocyte adhesion to the endothelium of aorta and carotid artery of rats. 753 42

The role of tissue factor (TF) as an initiator of the thrombotic complications secondary to atherosclerosis has been acknowledged, and in situ expression of TF activity by monocyte-derived macrophages and lesion-associated macrophage foam cells has been documented. Macrophages express TF activity upon exposure in vitro to either oxidized low density lipoprotein LDL (Ox-LDL) or endotoxin (lipopolysaccharide). This activity has been associated with membrane vesicles that apparently are shed after procoagulant expression. The present study based upon the correlative use of an enzyme-linked coagulant assay and three-dimensional multi-antigen, immunogold electron microscopy, reports the ultrastructural localization of TF antigen and spatially correlates TF with OX-LDL binding and the presence of nascent fibrin polymers on the plasma membrane of cultured macrophages. Pigeon monocyte/macrophages, after a 4-hour induction with lipopolysaccharide (2 micrograms/ml) or minimally oxidized LDL (50 micrograms/ml; thiobarbituric acid reducing substance, 5 to 8 nmol/mg protein) were incubated for 40 minutes in a Tris-buffered medium containing factors VII, V, X, II, and I before either assaying for coagulant activity or processing for gold-colloid cytochemistry. TF activity, as measured by enzyme-linked coagulant assay peaked 6 hours after agonist exposure with lipopolysaccharide and Ox-LDL giving, respectively, 115- and 60-fold stimulation as compared with control. This activity corresponded to the elaboration of membrane ruffles and microvilli on the cell surfaces. Through correlative immunogold cytochemistry (15-nm-diameter colloid) and gold-ligand cytochemistry (30-nm-diameter colloid), TF antigen (83%) and Ox-LDL (78%) were primarily associated with the membrane ruffles and microvilli. Multi-antigen immunogold cytochemistry when used in conjunction with ligand-gold cytochemistry documented co-localization of Ox-LDL (22-nm gold), TF antigen (15-nm gold) and a delicate three-dimensional network of short fibrin fibers that were decorated in a linear fashion with the immunogold probes (30-nm gold). These results provide evidence that TF antigen is located at selected regions on the cell surfaces. Furthermore, these same regions provide binding sites for agonist uptake and organization sites for fibrin polymerization. Hypothetically, the localized membrane regions could be shed from the cell surface as a means for regulating coagulation potential.
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PMID:Procoagulant activity after exposure of monocyte-derived macrophages to minimally oxidized low density lipoprotein. Co-localization of tissue factor antigen and nascent fibrin fibers at the cell surface. 757 48

The tissue factor (TF) gene is expressed in a cell type-specific manner in vivo. It is constitutively expressed by several extravascular cell types and inducibly expressed within the vasculature by monocytes and endothelial cells. TF expression initiates thrombotic episodes associated with various diseases, including atherosclerosis, septic shock, and cancer. Regulatory elements within the human TF promoter have been identified by functional analysis of TF promoter-luciferase gene plasmids transiently transfected into various cell types. Transcription factors that control expression of the TF gene were identified using gel shift mobility assays. Induction of the TF gene in human monocytic cells and endothelial cells exposed to bacterial lipopolysaccharide or cytokines is mediated by a distal enhancer (-227 to -172 bp) containing two AP-1 sites and a kappa B site. Functional interactions between Fos-Jun heterodimers and c-Rel-p65 heterodimers are required for transcriptional activation of the TF gene. In contrast, serum and phorbol ester induction of the TF gene in human epithelial cells is controlled by a proximal enhancer (-111 to +14 bp) containing three overlapping Egr-1/Sp1 binding sites. Sp1 is constitutively expressed whereas Egr-1 expression is induced by serum or phorbol ester stimulation. Sp1 also mediates basal promoter activity. Thus, TF gene expression is complex and is regulated by a number of transcription factors that bind to distinct regions of the TF promoter.
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PMID:Regulation of the tissue factor gene. 761 58

Oxidative stress and expression of the vascular cell adhesion molecule-1 (VCAM-1) on vascular endothelial cells are early features in the pathogenesis of atherosclerosis and other inflammatory diseases. Regulation of VCAM-1 gene expression may be coupled to oxidative stress through specific reduction-oxidation (redox) sensitive transcriptional or posttranscriptional regulatory factors. In cultured human umbilical vein endothelial (HUVE) cells, the cytokine interleukin 1 beta (IL-1 beta) activated VCAM-1 gene expression through a mechanism that was repressed approximately 90% by the antioxidants pyrrolidine dithiocarbamate (PDTC) and N-acetylcysteine (NAC). Furthermore, PDTC selectively inhibited the induction of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1), mRNA and protein accumulation by the cytokine tumor necrosis factor-alpha (TNF alpha) as well as the noncytokines bacterial endotoxin lipopolysaccharide (LPS) and double-stranded RNA, poly(I:C) (PIC). PDTC also markedly attenuated TNF alpha induction of VCAM-1-mediated cellular adhesion. In a distinct pattern, PDTC partially inhibited E-selectin gene expression in response to TNF alpha but not to LPS, IL-1 beta, or PIC. TNF alpha and LPS-mediated transcriptional activation of the human VCAM-1 promoter through NF-kappa B-like DNA enhancer elements and associated NF-kappa B-like DNA binding proteins was inhibited by PDTC. These studies suggest a molecular linkage between an antioxidant sensitive transcriptional regulatory mechanism and VCAM-1 gene expression that expands on the notion of oxidative stress as an important regulatory signal in the pathogenesis of atherosclerosis.
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PMID:Vascular cell adhesion molecule-1 (VCAM-1) gene transcription and expression are regulated through an antioxidant-sensitive mechanism in human vascular endothelial cells. 769 89

Monokines, including tumor necrosis factor alpha (TNF-alpha), have been implicated in the pathogenesis of several pathologic processes, including atherosclerosis. Because estrogen has been found to offer a certain degree of protection against atherosclerotic progression, we examined the effect of estrogen on the expression of TNF-alpha mRNA in a monocyte-macrophage cell line, THP-1. Cells were exposed to 12-O-tetradecanoylphorbol 13-acetate (TPA, 50 ng/ml) for 48 or 96 h to induce differentiation. Some of the cells were treated with lipopolysaccharide (LPS, 10 micrograms/ml) in the last 3 h and/or ethinyl estradiol (estrogen, 10(-9) M) in the last 20 h. Total cellular RNA was isolated and cDNA synthesized and than coamplified using the polymerase chain reaction (PCR) in the presence of two sets (pairs) of 32P-labeled primers, one for TNF-alpha (product size 325 bp) and the second for the internal control, glyceraldehyde 3-phosphate dehydrogenase (G3PDH; 983 bp). The resultant PCR products were separated by agarose gel electrophoresis, and the ratios of radioactivity incorporated into TNF-alpha PCR products to G3PDH products were used to assess the relative changes in the levels of TNF-alpha mRNA abundance in response to various substances. Treatment with TPA for 48 h induced the expression of TNF-alpha mRNA. Treatment of these TPA-stimulated cells with estrogen caused a 62% decrease in TNF-alpha message abundance (p < 0.01). Similar results were obtained with cells stimulated with TPA for 96 h.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Estrogen modulates the expression of tumor necrosis factor alpha mRNA in phorbol ester-stimulated human monocytic THP-1 cells. 770 11

P388D1 macrophage-like cells have previously been shown to produce both mitogenic and inhibitory regulators of porcine smooth muscle cell (pSMC) growth. The mitogenic activity was shown to have a molecular mass of > 10 kDa while the inhibitory activity was in the range of 2-6 kDa. In the present study, we present a novel dialysis culture system where P388D1 cells were grown in dialysis membranes with a 12 kDa cut-off which allowed continuous production of fractions of the culture medium. Using pSMC as target cells, mitogenic activity was found to be retained by the dialysis membrane while the low molecular mass inhibitory activity passed freely through the membrane. The effect of the macrophage-activators phorbol myristate acetate (PMA), concanavalin A (ConA) and interferon-gamma in combination with lipopolysaccharide (IFN gamma/LPS) were investigated in the dialysis culture system. PMA, ConA and IFN gamma/LPS were found to enhance the production of mitogenic activity by P388D1 cells. PMA also increased the production of growth-inhibitory activity, while ConA abolished inhibitor production and IFN gamma/LPS had no effect on the amount of inhibitory activity produced by P388D1 cells. The experiments show that the balance of production of mitogenic and inhibitory activities by macrophages can be modulated by agents that alter the state of activation of the cells. This could be of profound significance in the influence of macrophages on smooth muscle cell growth during the development of atherosclerosis.
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PMID:A dialysis culture system for the study of the production and modulation of growth-regulatory molecules: studies using the P388D1 macrophage cell line. 773 13

Increased monocyte adhesion to aortic endothelium is observed in the pathogenesis of atherosclerosis. The role of endothelial acyl-coenzyme A:cholesterol-acyltransferase (ACAT) in the regulation of monocyte adhesion is not known. To examine the potential role of this enzyme in monocyte adhesion, a specific ACAT inhibitor, CI-976, was utilized. Although the basal adhesion of U937 monocytic cells to porcine aortic endothelial cells was low, treatment of the endothelial cells with lipopolysaccharide (LPS) markedly increased monocyte adhesion. Monocyte adhesion to LPS-treated endothelial cells was markedly inhibited by CI-976 treatment of the endothelial cells. Similarly, another ACAT inhibitor, PD 132301-2, whose structure is distinct from CI-976, also decreased monocyte adhesion. CI-976 treatment of endothelial cells also decreased endothelial cell ACAT activity. Since leukotriene B4 (LTB4) is known to promote leukocyte-endothelial cell adhesion, endothelial cell production of this leukotriene was examined after incubation with CI-976. CI-976 treatment markedly decreased LTB4 synthesis. Exogenous LTB4 addition to CI-976 treated cells reversed the effects of this compound on monocyte adhesion. These data demonstrate that ACAT inhibitors decrease monocyte adhesion to endothelial cells. Similar mechanisms may contribute to antiatherosclerotic effects of ACAT inhibitors in vivo.
Atherosclerosis 1995 Jan 06
PMID:Acyl-coenzyme A:cholesterol-acyltransferase (ACAT) inhibitors modulate monocyte adhesion to aortic endothelial cells. 777 69

The fibrinolytic potential of the endothelial cells gives important antithrombotic properties to the vascular wall. Thrombosis is a frequent complication to atherosclerosis and other conditions where inflammatory mediators are present in the vascular wall. Inflammatory agents like lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF alpha) have been demonstrated to modulate the expression of fibrinolytic factors in cultured endothelial cells. In the present study the expression of tissue-type plasminogen activator (t-PA), urokinase plasminogen activator (u-PA) and plasminogen activator inhibitors-1 and -2 (PAI-1 and PAI-2) antigen in conditioned medium from cultured human umbilical vein (HUVEC) and human saphenous vein (HSVEC) endothelial cells was investigated under basal conditions and after stimulation with LPS, TNF alpha, interferon-gamma (IFN-gamma) or interleukin-6 (IL-6) alone or in combinations. Stimulation with LPS or TNF alpha increased the expression of PAI-1, u-PA and PAI-2 in HUVEC and HSVEC, while the t-PA response differed between the two cell types. The effects of TNF alpha were modulated by IFN-gamma but not by IL-6. The increased expression of u-PA after stimulation with TNF alpha was reduced by IFN-gamma. In contrast, TNF alpha-induced expression of PAI-2 was synergistically increased by addition of IFN-gamma. These effects of IFN-gamma represent additional mechanisms by which inflammatory mediators may turn the fibrinolytic potential of the endothelium in a prothrombotic direction.
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PMID:Interferon-gamma modulates the fibrinolytic response in cultured human endothelial cells. 777 58

Curcumin, contained in the rhizome of the plant Curcuma longa Linn, is a naturally occurring phytochemical that has been used widely in India and Indonesia for the treatment of inflammation. The pleiotropic cytokine tumor necrosis factor-alpha (TNF) induces the production of interleukin-1 beta (IL-1), and, together, they play significant roles in many acute and chronic inflammatory diseases. They have been implicated in the pathogenesis of intracellular parasitic infections, atherosclerosis, AIDS and autoimmune disorders. This report shows that, in vitro, curcumin, at 5 microM, inhibited lipopolysaccharide (LPS)-induced production of TNF and IL-1 by a human monocytic macrophage cell line, Mono Mac 6. In addition, it demonstrates that curcumin, at the corresponding concentration, inhibited LPS-induced activation of nuclear factor kappa B and reduced the biological activity of TNF in L929 fibroblast lytic assay.
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PMID:Inhibition of tumor necrosis factor by curcumin, a phytochemical. 778 95

Monocyte-derived foam cells figure prominently in rupture-prone regions of atherosclerotic plaques. Peripheral blood monocytes in culture can produce certain enzymes that degrade extracellular matrix, known as matrix metalloproteinases (MMPs). Lipid-laden macrophages may thus contribute to weakening of extracellular matrix of rupture-prone atherosclerotic plaques. However, the spectrum and regulation of MMP production by foam cells remain unknown. To investigate this issue, we isolated lipid-laden macrophages from rabbit aortic lesions produced by a combination of hypercholesterolemia and balloon injury. Freshly isolated aortic macrophage foam cells, identified using cell-specific antibodies, contained immunoreactive stromelysin and interstitial collagenase, whereas alveolar macrophages isolated from the lungs of same rabbits did not. Macrophages from both tissue sources released gelatinolytic activity consistent with the 92-kDa gelatinase. In vitro, lipid-laden aortic macrophages, but not alveolar macrophages, synthesized de novo and released immunoprecipitable stromelysin and collagenase, with or without stimulation by phorbol ester or bacterial lipopolysaccharide. These stimuli caused foam cells to release additional gelatinolytic activity that migrated faster than a purified preparation of 92-kDa gelatinase in substrate-containing polyacrylamide gels, indicating activation of the 92-kDa gelatinase or induction of the 72-kDa gelatinase. Our results show that lipid-laden macrophages elaborate MMPs capable of degrading the major constituents of vascular extracellular matrix even without further stimulation. Therefore, these cells may contribute to remodeling of the extracellular matrix during atherogenesis and to the disruption of plaques often responsible for acute clinical manifestations of atherosclerosis.
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PMID:Macrophage foam cells from experimental atheroma constitutively produce matrix-degrading proteinases. 783 Dec 99


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