UMLS:C0004153 - FACTA Search

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Query: UMLS:C0004153 (atherosclerosis)
77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously demonstrated that mouse cytomegalovirus (MCMV) aggravates atherosclerosis in apolipoprotein E knockout (apoE(-/-)) mice, most likely by enhancing both systemic and local (e.g. in the vascular wall) cytokine production. However, until now it was unclear which cell type is responsible for this enhanced pro-inflammatory cytokine production. In this study we focused on the macrophage (mPhi), which besides being an important source of such cytokines, is known to be an important player in both atherosclerosis and viral clearance. We investigated whether MCMV could induce a pro-inflammatory immune mPhi phenotype, which ultimately may contribute to the development of atherosclerosis. To this end, peritoneal exudate cells (PEC) were elicited in apoE(-/-) mice by either MCMV or thioglycolate injection, and mPhi were phenotyped at 1 week post-intraperitoneal injection. MCMV-induced peritoneal mPhi contained MCMV DNA but had limited MCMV mRNA expression, indicating latent infection. These mPhi showed increased production of interferon-gamma (IFNgamma), exclusive production of interleukin-18 (IL-18) and increased expression of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86, when compared with thioglycolate-induced mPhi. From these results, we conclude that intraperitoneal injection of MCMV induces an immune-responsive exudate in which at 7 days post-infection, MCMV-infected mPhi express a pro-inflammatory immune phenotype. As such, the MCMV-induced mPhi may be an important player in aggravating atherosclerosis through systemic and/or local immune activation.
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PMID:Murine cytomegalovirus infection directs macrophage differentiation into a pro-inflammatory immune phenotype: implications for atherogenesis. 1538 Jul 74

Inflammation plays a pivotal role in the formation of atherosclerosis. In addition to being a risk marker for cardiovascular diseases, the role of C-reactive protein (CRP) in atherogenesis has been supported by more recent data. CD40-CD40L system is proven to be an important mediator of several auto-immune and chronic inflammation diseases. Interruption of CD40-CD40L signaling pathway not only reduces the initiation and progression of atherosclerotic lesions, but also modulates plaque architecture. By using a flow cytometry and western blotting, we found that incubation of human umbilical vein endothelial cells (HUVECs) with CRP resulted in a time- and dose-dependent increase in the cell-surface expression of CD40 and CD40L. In addition, CRP (25 microg/ml) increased gelatinolytic activities of MMP-2 and MMP-9. Anti-CD40 antibody significantly reversed the upregulated activities of MMP-2 and MMP-9 induced by CRP with gelatin zymography. Furthermore, lovastatin (10(-7), 10(-6), 10(-5) mol/l) and fenofibrate (5 x 10(-5), 10(-4), 2 x 10(-4) mol/l) significantly diminished the expression of CD40, CD40L and gelatinase activities (MMP-2, MMP-9) induced by CRP in HUVECs. In conclusion, our data provide evidence to support the direct pro-inflammatory effects of CRP via CD40-CD40L signaling pathway involved in the pathogenesis of atherosclerosis, and lovastatin and fenofibrate possess anti-inflammatory effects independent of their lipid-lowering action.
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PMID:C-reactive protein-induced expression of CD40-CD40L and the effect of lovastatin and fenofibrate on it in human vascular endothelial cells. 1546 91

The understanding of the pathophysiology governing atherosclerosis supports a prominent role for inflammation pathways in plaque initiation and progression that result in stroke and myocardial infarction. Elevated levels of inflammatory markers in the blood, such as C-reactive protein and CD40 ligand/CD40, in concert with increased expression of adhesion molecules, chemokines, cytokines, matrix metalloproteinases (MMP), and inflammatory cells in the plaque, characterize the symptomatic atherothrombotic state. Advances in predictive capabilities of vascular events using a number of these biomarkers are beginning to remodel our clinical practice in the use of medications such as statins and angiotensin receptor blockers for stroke prevention. Although the general inflammatory features of atherosclerosis are becoming widely recognized, factors resulting in individual variability in plaque formation and instability remain poorly defined. Emerging literature points toward several acquired and innate susceptibility factors in the immune pathways that may provide insight into why many plaques rapidly evolve from a "stable" to an "unstable" or symptomatic state. First, exposure of plaque memory T-lymphocytes to infectious or endogenous antigens may result in rapid clonal expansion of T-cell variable beta chain subtypes and stimulate macrophages to release MMPs, causing plaque destabilization. The effects of infectious agents can further be influenced by an individual's major histocompatibility complex class II molecule profiles, which can affect susceptibility to specific organisms. Second, functional polymorphisms of genes that regulate the immune pathway can predispose patients to a more robust inflammatory expression after risk factor exposure. Identification of a susceptibility gene profile and immunologic mediators that promote T-cell activation provides a unique opportunity for early identification of stroke risk and targets for future therapy.
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PMID:Immunogenetic susceptibility of atherosclerotic stroke: implications on current and future treatment of vascular inflammation. 1547 6

Patients with rheumatoid arthritis (RA) have a two to five times increased risk of developing premature cardiovascular disease that shortens life expectancy by 5-10 years. Traditional risk factors known to promote and accelerate the progression of atherosclerotic lesions however, are often absent in patients with RA. Many similarities have emerged between the paradigm of inflammation in the pathogenesis of atherosclerosis and the well-established mechanisms of inflammation in the pathogenesis of RA. Hence it is intriguing to speculate that inflammation in RA is not confined to the joints but also present in the vessel wall. Indeed, low-grade inflammation and endothelial dysfunction play pivotal roles in the initiation, progression and propagation of the atherosclerotic process. While the healthy endothelium prevents adhesion of mononuclear cells, the defence mechanisms cease under the influence of cardiovascular risk factors and inflammation and they express adhesion molecules (selectins, vascular adhesion molecule-([VCAM-]1, intercellular adhesion molecule-[ICAM-]1) that promote the adherence of monocytes. This expression is induced by pro-inflammatory cytokines such as interleukin-(IL-)1beta and tumor necrosis factor-(TNF-)alpha, by C-reactive protein (CRP), and CD40/CD40 ligand interactions. As all of these factors are present at increased levels in the systemic circulation in RA, it appears possible that they might impact the endothelium as well. Further similarities include proteolytic enzymes such as matrix metalloproteinases (MMPs) that play a role in joint destruction as well as in destabilization and rupture of vulnerable atherosclerotic plaques. In addition, coagulation factors such as increased levels of tissue factor (TF), van Willebrand factor (vWF) and plasminogen activator inhibitor-(PAI-)1 are important in both, RA and CAD. Endothelial dysfunction has shown to correlate with cardiovascular prognosis in several studies, which indicates its clinical relevance. Endothelial function measurement is performed in the coronary or peripheral circulation (by venous occlusion plethysmography or flow-mediated dilation). Recent studies have demonstrated impaired endothelial function in patients with RA, already at early stages of the disease. Similar results are found in patients with systemic lupus erythematosus (SLE), indicating that inflammation per se may impair altering vascular function. This and more evidence supports the notion that inflammation plays a pivotal role in vascular dysfunction and may by these mechanisms explain at least part of the excess morbidity and mortality observed in RA and SLE. In light of the growing evidence of increased cardiovascular morbidity and mortality mostly independent of traditional risk factors, treatment strategies in RA should not only aim at relieving symptoms and inhibiting joint destruction but should have a beneficial effect on the vasculature to reduce cardiovascular events. Indeed, an improvement in endothelial function in RA was recently demonstrated by anti-TNF-alpha therapy and statins. Whether and to what degree the effects of anti-inflammatory strategies to improve endothelial function, which although clinically well established is still a surrogate, translate into clinical benefit for our patients with rheumatologic diseases needs to be determined in large-scale clinical trials some of which are now already under way.
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PMID:[Rheumatoid arthritis, inflammation, and atherosclerosis]. 1559 72

Increasing evidence shows the importance of platelet-endothelial cell interactions in the progression of atherosclerosis. Platelets contribute to coronary events both as major components of thrombi and as a triggering factor in inflammation that leads to plaque vulnerability. Recent data suggest that statins, besides their lipid-lowering properties, exert pleiotropic effects that may be beneficial in atherosclerosis. Whether activated platelets influence cyclooxygenase-2 (COX-2) expression in human umbilical vein endothelial cells (HUVEC), the effect of atorvastatin, and possible mechanisms were investigated. COX-2 gene expression in HUVEC was studied using real-time polymerase chain reaction. CD40 ligand surface expression of platelets was tested by fluorescence-activated cell sorting analyses. Activated platelets significantly up-regulated COX-2 gene expression in HUVEC. Co-incubation of platelets with atorvastatin was shown to reverse this up-regulation via reduction of CD40 ligand surface expression on platelets. Data suggest that atorvastatin influences CD40-CD40-ligand-dependent platelet-endothelial interaction and that this influence affects platelet-induced COX-2 expression in HUVEC.
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PMID:CD40-ligand-dependent induction of COX-2 gene expression in endothelial cells by activated platelets: inhibitory effects of atorvastatin. 1574 97

Large increases in mortality related to premature atherosclerosis with coronary artery disease and stroke have been reported during the last few years in patients with systemic lupus erythematosus (SLE). Studies found relative risks of 5 to 7 for myocardial infarction in SLE patients. The traditional risk factors fail to fully account for accelerated atherosclerosis in SLE and APS, in addition prolonged glucocorticoid therapy and long duration of SLE seem to be of importance. The disease SLE per se is an independent risk factor. The current pathogenic hypothesis for atherosclerosis involves an inflammatory response, autoantibodies, immune complexes (containing antibodies to phospholipids, to oxidized LDLs, and to endothelial cells), CD40/CD40 ligand interactions, and bacterial or viral infections responsible for an immune response. The determination of classic and new risk factors, together with specific autoantibody titers and the use of Doppler carotid ultrasound, are useful methods to detect early atherosclerosis. Therapeutic strategies, including early risk factor intervention and effective control of inflammation, are essential to reduce morbidity and mortality and should be incorporated into the management of connective tissue disease with the goal of protecting patients against atherosclerosis.
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PMID:[Accelerated atherosclerosis in rheumatic systemic diseases as an example of systemic lupus erythematosus--what is the consequence?]. 1590 83

There is a growing body of evidence that dihydropyridine-based calcium antagonists (DHPs) improve endothelial function, thus slowing the development and progression of atherosclerosis. We have previously shown that nifedipine, one of the most popular DHPs, inhibits tumor necrosis factor-alpha (TNF-alpha)-induced reactive oxygen species generation and subsequent monocyte chemoattractant protein-1 (MCP-1) expression in human umbilical vein endothelial cells (HUVEC). However, the molecular mechanism underlying this phenomenon remains to be elucidated. CD40, a cell surface receptor that belongs to TNF-alpha receptor, has been associated with the pathogenesis of chronic inflammatory diseases such as atherosclerosis. In this study, we investigated the involvement of CD40 in MCP-1 suppression by nifedipine in TNF-alpha-exposed HUVEC. Nifedipine completely inhibited TNF-alpha-induced upregulation of CD40 mRNA levels in HUVEC. Furthermore, antibody against human CD40 was found to significantly inhibit upregulation of MCP-1 mRNA levels in TNF-alpha-exposed HUVEC. These results demonstrate that nifedipine could inhibit the TNF-alpha-induced upregulation of MCP-1 mRNA levels via suppression of CD40 expression in HUVEC. Our present study suggests that blockade of CD40 signaling in endothelial cells may be a molecular target for the vasculoprotective property of nifedipine.
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PMID:Nifedipine inhibits tumor necrosis factor-alpha-induced upregulation of monocyte chemoattractant protein-1 mRNA levels by suppressing CD40 expression in endothelial cells. 1592 Oct 25

The discovery that platelets express CD40 and the CD40 ligand has transformed these cells, once seen as exclusively involved in coagulation and thrombosis, into active players of immunity and inflammatory injury. Many of the broad and potent biological activities mediated through the CD40/CD40 pathway by immune and nonimmune cells are also exerted by activated platelets. This occurs either through the constitutive expression of CD40 on the platelet surface or the activation-induced expression of the CD40 ligand, which is membrane bound and released from the surface in a soluble form. The most prominent activities mediated by the platelet CD40/CD40 ligand pathway include inflammatory, immunoregulatory, and hemostatic functions, all of which contribute to the newly expanded view of platelets as key biological mediators involved in disease processes such as atherosclerosis, inflammatory bowel disease, and diabetes. Therefore, considering platelet CD40 and CD40 ligand as novel biological targets is justified and supported by animal studies. The clinical profit to be gained from blocking this molecular pair will be determined by results in humans with conditions in which the platelet CD40/CD40 ligand pathway is crucially involved in disease pathogenesis.
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PMID:Platelet activation and the CD40/CD40 ligand pathway: mechanisms and implications for human disease. 1595 32

Inhibition of CD40-CD40L interactions results in a reduction of innate regulatory T cells (Tregs) in CD40(-/-) mice and induces a stable plaque phenotype in atherosclerosis-prone mouse strains. Here we investigated the effects of leukocyte CD40L on the Treg population and on atherosclerosis. LDLR(-/-) mice were reconstituted with wild-type or CD40L(-/-) bone marrow (BM). These BM chimeras were analysed by flow cytometry for the presence of innate Tregs (CD45RB(low) CD25(+) CD4) in lymphoid organs and peripheral blood. As in CD40(-/-) mice, the CD45RB(high):CD45RB(low) CD4 T cell ratio significantly increased and the CD25(+) CD4(+) subpopulation significantly decreased in LDLR(-/-) mice receiving CD40L(-/-) BM compared to LDLR(-/-) mice receiving wild-type BM. However, atherosclerotic plaque progression and plaque phenotype did not change in LDLR(-/-) mice reconstituted with CD40L(-/-) BM. In conclusion, the present study shows that CD40-CD40L interactions on leukocytes are essential for the size of the CD45RB(low) CD25(+) CD4 Treg subpopulation. Nevertheless, CD40L deficiency on hemopoietic cells did not affect atherosclerosis, implying that CD40L expressing leukocytes alone are not responsible for the stable plaque phenotype observed after total CD40L blockade.
Atherosclerosis 2005 Dec
PMID:Leukocyte CD40L deficiency affects the CD25(+) CD4 T cell population but does not affect atherosclerosis. 1600 76

The role of C-reactive protein (CRP) in atherogenesis has been supported by more recent data. Some studies have demonstrated marked up-regulation inflammatory responses in endothelial cells subjected to CRP. The nuclear factor-kappaB (NF-kappaB) signal transduction is known to play a key role in the expression of these proatherogenic entities. Statins have anti-inflammatory properties independent of their cholesterol-lowering effects. Therefore, we studied the effects of CRP and lovastatin on NF-kappaB activation in human umbilical vein endothelial cells (HUVECs). By using an electrophoretic mobility shift assays (EMSA), we found that CRP (50 microg/ml) increased activation of NF-kappaB and degradation of inhibitory kappa B (IkappaB) in HUVECs, reaching a maximal effect after the incubation with CRP for 1 h. Lovastatin (10(-5) mol/l) diminished NF-kappaB activation induced by CRP. Furthermore, lovastatin may block NF-kappaB activation by causing a stabilization of the IkappaB-alpha in cellular cytoplasm with western blotting analysis. Preincubation of HUVECs with pyrrolidinethiocarbamate (PDTC, NF-kappaB inhibitor) diminished CD40 expression induced by CRP with flow cytometry. Our results suggest that CRP increases activation of NF-kappaB and induces CD40 expression in HUVECs partly via activation of NF-kappaB. Lovastatin, through the inhibition of NF-kappaB activation, reduces the inflammation involved in the pathogenesis of atherosclerosis.
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PMID:Lovastatin reduces nuclear factor kappaB activation induced by C-reactive protein in human vascular endothelial cells. 1614 29

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