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)

Probucol is a clinically important drug that decreases plasma cholesterol in humans and has a marked anti-atherogenic effect in hyperlipidaemic Watanabe rabbits. The action of probucol in this animal model has been partly attributed to its anti-oxidant abilities. Probucol can decrease the oxidative modification of low-density lipoprotein and hence diminish its uptake by macrophages. In this paper, we have examined the effect of probucol on the monoblastic cell line U937 and on U937 cells induced to differentiate towards a macrophage phenotype by 1,25-dihydroxycholecalciferol (DHCC), tumour necrosis factor-alpha (TNF-alpha) or phorbol myristate acetate (PMA). We found that probucol enhanced the proliferation of undifferentiated U937 cells. Probucol also enhanced proliferation in cultures that had been pre-treated with DHCC or TNF-alpha, but had no effect on cultures that had been pre-treated with PMA. In contrast, when U937 cells were treated simultaneously with probucol and DHCC or TNF-alpha, there was a more marked decrease in proliferation than was induced by these agents in the absence of probucol. Probucol had little effect on the phenotype of resultant cells. The surface expression of CD13 (aminopeptidase N), CD4, CD35 (C3b receptor), CD64 (Fc gamma RI), CD71 (transferrin receptor) and HLA Class II was not affected by probucol. Probucol treatment led to a small increase in the surface expression of CD16 (Fc gamma RIII) in TNF-alpha treated cells and to a small decrease in the expression of CD14 (a monocyte marker) in PMA-treated cells. The induction of c-fgr mRNA and TNF-alpha mRNA by DHCC or PMA or TNF-alpha was not significantly altered in the presence of probucol. The affect of probucol on U937 cells does not appear to be due to its anti-oxidant abilities because butylated hydroxytoluene (BHT), an equally powerful anti-oxidant, did not have the same effect on the cell proliferation as probucol and because no changes were detected in the levels of lipid peroxidation in U937 cell culture supernatants.
Atherosclerosis 1993 Feb
PMID:Effects of the synthetic anti-oxidant, probucol, on the U937 monoblastoid cell line. 846 Oct 53

Mononuclear phagocytes play a major role in the development of vascular lesions in atherogenesis. The goal of our study was to characterize circulating blood monocyte subpopulations as potential cellular markers of systemic immunological abnormalities in hypercholesterolemia. In normal subjects, three-parameter immunophenotyping of whole blood revealed that 61.3 +/- 6.0% of monocytes showed "bright" expression of the lipopolysaccharide receptor (LPSR: CD14) and Fc gamma receptor I (RI: CD64) without expression of Fc gamma-RIII (CD16). Other monocyte subsets (populations 2, 3, 4, and 5) were characterized by the simultaneous expression of both Fc gamma-R's (25.6 +/- 5.0%), isolated expression of Fc gamma-RIII (9.4 +/- 1.7%), or high expression of CD33 (3.7 +/- 1.1%) with only dim expression of CD14, respectively. The smallest subset of monocytes (population 5: 2.1 +/- 0.8%) differed from the predominant population of CD14brightCD64+CD16- monocytes by additional expression of neural cell adhesion molecule (N-CAM: CD56). In a group of hypercholesterolemic patients (n = 19), high density lipoprotein cholesterol levels were negatively correlated to the population size of CD64-CD16+ monocytes. In both healthy subjects (n = 55) and hypercholesterolemic patients, the rare apolipoprotein E3/E4 and E4/E4 phenotypes were associated with a tendency toward a larger population of CD64-CD16+ monocytes. Expression of the variant activation antigen CD45RA by peripheral blood mononuclear phagocytes showed a positive correlation to plasma levels of the atherogenic lipoproteins low density lipoprotein and lipoprotein(a). These data suggest that systemic abnormalities in mononuclear phagocyte subpopulations may play a role in the pathogenesis of atherosclerosis.
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PMID:Peripheral blood mononuclear phagocyte subpopulations as cellular markers in hypercholesterolemia. 897 47

The incubation of human macrophages with antigen antibody complexes prepared with rabbit anti-LDL and human LDL (LDL-IC) is followed by ingestion of those immune complexes (IC), massive cholesterol ester accumulation, cytokine release and overexpression of the LDL receptor. The massive accumulation of cholesterol esters and overexpression of the native LDL receptor are specifically induced by immune complexes containing native or modified LDL, but not by any other type of IC. We report the results of a series of experiments aimed at defining the receptor preferentially involved in LDL-IC uptake. Flow cytometry studies using CD16, CD32 and CD64 monoclonal antibodies showed a sharp reduction on the expression of CD64 (Fc gamma RI) both by human monocyte-derived macrophages and THP-1 cells after incubation with LDL-IC, suggesting preferential engagement of this type of Fc receptor. Blocking experiments with aggregate-free IgG1 and CD32 monoclonal antibody confirmed that blocking Fc gamma RI prevented both LDL-IC uptake and the upregulation of LDL receptors on THP-1 cells. In contrast, blocking Fc gamma RII did not affect either the uptake of LDL-IC or the expression of LDL receptors on the same cells. The preferential engagement of Fc gamma R-I by LDL-IC suggests a biological difference of LDL-IC relative to other types of IC and opsonized particles. The precise molecular mechanism(s) responsible for the paradoxical upregulation of LDL receptor after the uptake of LDL-IC remain to be elucidated.
Atherosclerosis 1997 Dec
PMID:The uptake of LDL-IC by human macrophages: predominant involvement of the Fc gamma RI receptor. 943 Mar 65

Obstructive sleep apnea (OSA) is associated with increased cardiovascular morbidity and mortality. Free radicals and adhesion molecules were implicated in the pathogenesis of atherosclerosis leading to cardiovascular disorders. Therefore, we investigated the link between CD15, CD11c, CD11b, and CD64 expression on leukocytes and their ability to generate reactive oxygen species (ROS) in patients with OSA and control volunteers. We also studied the effects of hypoxia in vitro on monocytes from control subjects and the ability of monocytes from both groups to adhere to human endothelial cells in culture. The effect of nasal continuous positive airway pressure (nCPAP) treatment was studied as well. We found that OSA was associated with increased expression of adhesion molecules CD15 and CD11c on monocytes, increased adherence of monocytes in culture to human endothelial cells, increased intracellular ROS production in some monocyte and granulocyte subpopulations, and upregulation of CD15 expression due to hypoxia in vitro in monocytes of control subjects. Furthermore, nCPAP treatment was associated with downregulation of CD15 and CD11c monocyte expression and decreased basal ROS production in CD11c+ monocytes. Monocyte adherence to endothelial cells decreased as well. Our findings provide one of the possible mechanisms for explaining the high rate of cardiovascular morbidity in patients with sleep apnea.
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PMID:Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. 1193 9

Activation of T lymphocytes and their ensuing elaboration of proinflammatory cytokines, such as interferon (IFN)-gamma, represent a critical step in atherogenesis and arteriosclerosis. IFNgamma pathways also appear integral to the development of transplantation-associated arteriosclerosis (Tx-AA), limiting long-term cardiac allograft survival. Although disruption of these IFNgamma signaling pathways limits atherosclerosis and Tx-AA in animals, little is known about inhibitory regulation of proinflammatory cytokine production in humans. The present study investigated whether activators of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma, with their known antiinflammatory effects, might regulate the expression of proinflammatory cytokines in human CD4-positive T cells. Isolated human CD4-positive T cells express PPARalpha and PPARgamma mRNA and protein. Activation of CD4-positive T cells by anti-CD3 monoclonal antibodies significantly increased IFNgamma protein secretion from 0 to 504+/-168 pg/mL, as determined by ELISA. Pretreatment of cells with well-established PPARalpha (WY14643 or fenofibrate) or PPARgamma (BRL49653/rosiglitazone or pioglitazone) activators reduced anti-CD3-induced IFNgamma secretion in a concentration-dependent manner. PPAR activators also inhibited TNFalpha and interleukin-2 protein expression. In addition, PPAR activators markedly reduced cytokine mRNA expression in these cells. Such antiinflammatory actions were also evident in cell-cell interactions with medium conditioned by PPAR activator-treated T cells attenuating human monocyte CD64 expression and human endothelial cell major histocompatibility complex class II induction. Thus, activation of PPARalpha and PPARgamma in human CD4-positive T cells limits the expression of proinflammatory cytokines, such as IFNgamma, yielding potential therapeutic benefits in pathological processes, such as atherosclerosis and Tx-AA.
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PMID:PPAR activators as antiinflammatory mediators in human T lymphocytes: implications for atherosclerosis and transplantation-associated arteriosclerosis. 1193 39

Chronic endothelial infection is believed to be one of the factors able to cause endothelial cell damage and trigger the onset of human atherosclerosis. Chlamydophila pneumoniae infects endothelial cells and has received special attention because of both epidemiological and experimental evidence supporting its role as a risk factor for atherosclerosis. It is also possible that otherwise independent risk factors for atherosclerosis may have synergistic effects. Immune phenomena, such as the formation of circulating immune complexes (IC) containing modified LDL and corresponding antibodies, have been linked to the development of coronary artery disease. The antibodies involved in the immune response to modified lipoproteins are predominantly of the pro-inflammatory IgG1 and IgG3 subclasses. However, it is difficult to understand how circulating IC could cause endothelial damage and initiate the atherosclerotic process, unless they were formed in the subendothelial space or immobilized by endothelial cells. The last hypothesis would be possible if endothelial cells expressed Fcgamma receptors. Healthy endothelial cells do not express Fcgamma receptors, but endothelial cells infected by a variety of infectious agents do. Thus we decided to investigate whether infection of endothelial cells with C. pneumoniae is also able to cause the expression of Fcgamma receptors. The expression of Fcgamma receptors (CD64, 32, and 16) on human aortic endothelial cells infected with C. pneumoniae for 4, 24, 36, and 48 h was studied by flow cytometry. Twenty-four hours after infection 30-40% of the endothelial cells had detectable inclusion bodies, 8-9% of the total number of cells (approximately 25% of the infected cells) expressed FcgammaRII, and about 1.5-2% (5% of infected cells) expressed FcgammaRI and FcgammaRIII. Double-staining studies confirmed that the expression of FcgammaRII was limited to C. pneumoniae-infected endothelial cells. We conclude that C. pneumoniae infection induces primarily the expression of FcgammaRII by endothelial cells and this may be a significant link between two proposed pathogenic mechanisms involved in the pathogenesis of human atherosclerosis.
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PMID:Chlamydophila pneumoniae infection of human aortic endothelial cells induces the expression of FC gamma receptor II (FcgammaRII). 1221 37

Generation of antibodies against oxidized-low-density lipoproteins (oxLDL) during atherosclerosis could result in the formation and deposition of oxLDL immune complexes (oxLDL-IC) on the vascular endothelial cells. Inflammatory cells express scavenger receptor (SR such as CD36) and Fcgamma receptor (FcgammaR: CD32A and CD64) that can bind to oxLDL and oxLDL-IC, respectively. Hence, depending on anti-oxLDL IgG titer, circulating monocytes could adhere to endothelium to oxLDL-IC-coated vascular bed via either FcgammaR and/or CD36. In this study, we determined the relative contribution of SR and FcgammaR in mediating monocyte interaction with oxLDL-IC deposited on vascular bed. At saturating levels of anti-oxLDL IgG concentration, monocytic cells adhered to oxLDL-IC and this adhesion is completely blocked by anti-CD32A mAb. Using CHOK1-CD32A-CD36 cells expressing equal levels of CD32A and CD36, it was observed that at lower concentrations of anti-oxLDL IgG, CD32A and CD36 contribute about 75% and 25% of cell adhesion, respectively, while at higher concentrations of anti-oxLDL IgG the adhesion is completely CD32A-dependent. CD32A-dependent adhesion was further confirmed with peripheral blood monocytes and platelets that express 2- to 5-fold higher levels of CD36 compared to CD32A. Further, PBMC adhesion to oxLDL-IC-deposited endothelial cells induced secretion of pro-inflammatory chemokines, MCP-1 and IL-8. Our results demonstrate that anti-oxLDL IgG blocks oxLDL interaction with SR such as CD36, whereas oxLDL-IC formation promotes monocyte adhesion and subsequent chemokine release through FcgammaR. These findings suggest a role for FcgammaR-mediated inflammatory cell activation in the progression of atherosclerosis.
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PMID:Anti-OxLDL IgG blocks OxLDL interaction with CD36, but promotes FcgammaR, CD32A-dependent inflammatory cell adhesion. 1708 22

C-reactive protein (CRP) is present in the atherosclerotic plaques and appears to promote atherogenesis. Intraplaque CRP colocalizes with oxidized low density lipoprotein (OxLDL) and macrophages in human atherosclerotic lesions. Matrix metalloproteinase-9 (MMP-9) has been implicated in plaque rupture. CRP promotes OxLDL uptake and MMP induction in vitro; however, these have not been investigated in vivo. We examined the effect of CRP on OxLDL uptake and MMP-9 production in vivo in Wistar rats. CRP significantly increased OxLDL uptake in the peritoneal and sterile pouch macrophages compared with human serum albumin (huSA). CRP also significantly increased intracellular cholesteryl ester accumulation compared with huSA. The increased uptake of OxLDL by CRP was inhibited by pretreatment with antibodies to CD32, CD64, CD36, and fucoidin, suggesting uptake by both scavenger receptors and Fc-gamma receptors. Furthermore, CRP treatment increased MMP-9 activity in macrophages compared with huSA, which was abrogated by inhibitors to p38 mitogen-activated protein kinase, extracellular signal-regulated kinase (ERK), and nuclear factor (NF)-kappaB but not Jun N-terminal kinase (JNK) before human CRP treatment. Because OxLDL uptake by macrophages contributes to foam cell formation and MMP release contributes to plaque instability, this study provides novel in vivo evidence for the role of CRP in atherosclerosis.
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PMID:Human C-reactive protein promotes oxidized low density lipoprotein uptake and matrix metalloproteinase-9 release in Wistar rats. 1824 17

Non-specific markers of inflammation such as C-reactive protein (CRP) are associated statistically with an increased risk of atherosclerosis through mechanisms that have not yet been fully elucidated. We investigated the effects of CRP on several aspects of human monocyte biology, a cell type involved in the initiation and progression of atherosclerosis. Blood monocytes isolated from healthy men and premenopausal women (n = 9/group) were exposed to purified CRP (25 microg/ml) for 12 hours. Changes in gene expression were analyzed using a custom-made array containing oligonucleotide sequences of 250 genes expressed by activated monocytes and confirmed by quantitative PCR. CRP increased significantly the expression of the cytokines interleukin (IL)-1alpha, IL-1beta and IL-6, and the chemokines GRO-alpha, GRO-beta and IL-8. CRP also displayed anti-inflammatory effects through upregulation of liver X receptor (LXR) alpha and activin receptor expression, and down-regulation of alpha 2-macroglobulin expression. Increased LXRalpha mRNA expression in both monocytes and the monocytic cell lineTHP-1 was associated with increased LXRalpha protein expression and nuclear translocation, as well as increased ABCA1 mRNA expression, a target gene of LXRalpha. Western blot analysis revealed CRP-induced nuclear translocation of NF-kappaB and activation of p42/44, MAP and Akt kinases. CRP-induced LXRalpha mRNA expression was inhibited by anti-CD64 (FcgammaRI) antibodies and by p42/44 and PI3 kinase inhibitors. This hypothesis-generating study demonstrates that CRP modulates the expression of genes that contribute to both pro- and anti-inflammatory responses in human monocytes. Among these novel anti-inflammatory effects, we show clearly that CRP activates the LXRalpha pathway.
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PMID:C-reactive protein induces pro- and anti-inflammatory effects, including activation of the liver X receptor alpha, on human monocytes. 1832 90

Several studies support C-reactive protein (CRP) as a systemic cardiovascular risk factor. The recent detection of CRP in arterial intima suggests a dual activity in atherosclerosis as a circulating and tissue mediator on vascular and immune cells. In the present paper, we focused on the inflammatory effects of CRP on human monocytes, which were isolated by Ficoll-Percoll gradients and cultured in adherence to polystyrene, endothelial cell monolayer, or in suspension. Chemokine levels, adhesion molecule, and chemokine receptor expression were detected by ELISA, flow cytometry, and real-time RT-PCR. Migration assays were performed in a Boyden chamber. Stimulation with CRP induced release of CCL2, CCL3, and CCL4 in adherent monocytes through the binding to CD32a, CD32b, and CD64, whereas no effect was observed in suspension culture. This was associated with CRP-induced up-regulation of adhesion molecules membrane-activated complex 1 (Mac-1) and ICAM-1 on adherent monocytes. Blockade of Mac-1/ICAM-1 interaction inhibited the CRP-induced chemokine secretion. In addition, CRP reduced mRNA and surface expression of corresponding chemokine receptors CCR1, CCR2, and CCR5 in adherent monocytes. This effect was a result of chemokine secretion, as coincubation with neutralizing anti-CCL2, anti-CCL3, and anti-CCL4 antibodies reversed the effect of CRP. Accordingly, a reduced migration of CRP-treated monocytes to CCL2 and CCL3 was observed. In conclusion, our data suggest an in vitro model to study CRP activities in adherent and suspension human monocytes. CRP-mediated induction of adhesion molecules and a decrease of chemokine receptors on adherent monocytes might contribute to the retention of monocytes within atherosclerotic lesions and recruitment of other circulating cells.
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PMID:C-reactive protein (CRP) induces chemokine secretion via CD11b/ICAM-1 interaction in human adherent monocytes. 1859 15


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