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)

Adhesion of leukocytes to the vascular endothelium is an early event in inflammation. Since cell-cell signaling may be an important stimulus for endothelial activation, we focused in this study on the role of contact-mediated activation by T lymphocytes of endothelial cells (EC). T lymphocytes were cultured with anti-CD3 monoclonal antibody or in the presence of a combination of TNF-alpha, interleukin (IL)-6, and IL-2, prior to fixation and coculture with human umbilical vein EC. Fixed, activated (anti-CD3- or cytokine-stimulated), but not unstimulated T cells, induced release of monocyte chemotactic protein-1, IL-8, and IL-6 by EC in a contact-dependent manner. Moreover, expression of tissue-factor antigen and activity was also significantly increased. Addition of anti-CD40 ligand antibody abolished T cell-induced activation of EC. Our data suggest that contact-mediated activation of EC by T cells, involving ligand:counter ligand interactions such as CD40:CD40 ligand, may represent a novel pathogenic mechanism of progression in inflammatory diseases such as atherosclerosis or rheumatoid arthritis.
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PMID:T cell-mediated signaling to vascular endothelium: induction of cytokines, chemokines, and tissue factor. 1192 53

Angiotensin II (ANG II) promotes vascular inflammation through nuclear factor-kappaB (NF-kappaB)-mediated induction of pro-inflammatory genes. The role of peroxisome proliferator-activated receptors (PPARs) in modulating vascular inflammation and atherosclerosis in vivo is unclear. The aim of the present study was to examine the effects of ANG II on PPARs and NF-kappaB-dependent pro-inflammatory genes in the vascular wall in an in vivo model of atherosclerosis and aneurysm formation. Six-month-old male apolipoprotein E-deficient (apoE-KO) mice were treated with ANG II (1.44 mg/kg per day for 30 days). ANG II enhanced vascular inflammation, accelerated atherosclerosis, and induced formation of abdominal aortic aneurysms. These effects of ANG II in the aorta were associated with downregulation of both PPAR-alpha and PPAR-gamma mRNA and protein and an increase in transcription of monocyte chemotactic protein-1 (MCP-1), macrophage-colony stimulating factor (M-CSF), endothelial-selectin (E-selectin), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) throughout the entire aorta. ANG II also activated NF-kappaB with increases in both p52 and p65 NF-kappaB subunits. In summary, these in vivo results indicate that ANG II, through activation of NF-kappaB-mediated pro-inflammatory genes, promotes vascular inflammation, leading to acceleration of atherosclerosis and induction of aneurysm in apoE-KO mice. Downregulation of PPAR-alpha and -gamma by ANG II may diminish the anti-inflammatory potential of PPARs, thus contributing to enhanced vascular inflammation.
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PMID:Angiotensin II is associated with activation of NF-kappaB-mediated genes and downregulation of PPARs. 1236 87

Atherosclerosis preferentially occurs in areas of turbulent flow and low fluid shear stress, while laminar flow and high shear stress are atheroprotective. Well characterized atheroprotective mechanisms include inhibition of thrombosis (increased tissue-type plasminogen activator and decreased plasminogen activator inhibitor-1), inhibition of endothelial cell apoptosis, limitation of permeability (uptake of low-density lipoprotein), prevention of white blood cell binding and transmigration (no expression of adhesion molecules such as intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1] and no release of monocyte chemotactic protein-1) and increased bioavailability of nitric oxide (because of increased expression of endothelial nitric oxide synthase and manganese superoxide dismutase). Our lab has investigated flow-mediated inhibition of inflammatory cytokine action. In particular, we have shown that flow prevents tumor necrosis factor-alpha (TNF-alpha) mediated signal transduction. TNF regulates inflammatory gene expression (e.g., ICAM-1 and VCAM-1) in endothelial cells, in part, by stimulating mitogen activated protein (MAP) kinases that phosphorylate transcription factors. We hypothesized that fluid shear stress inhibits TNF inflammatory effects on endothelial cells by inhibiting TNF mediated activation of the c-Jun N-terminal kinase. To test this hypothesis, we determined the effects of steady laminar flow on TNF-stimulated activity of c-Jun N-terminal kinase. The results show that flow inhibits c-Jun N-terminal kinase activation through multiple mechanisms, including stimulation of counter-regulatory MAP kinases (extracellular signal regulated kinases [ERK]1/2 and ERK5) and inhibition of apoptosis signal-regulated kinase. In summary, the atheroprotective effects of steady laminar flow on the endothelium involve multiple synergistic mechanisms. These multiple mechanisms offer attractive targets for new drug therapies aimed at limiting atherosclerosis development and progression. (c) 2002 Prous Science. All rights reserved.
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PMID:Atheroprotective Mechanisms Activated by Fluid Shear Stress in Endothelial Cells. 1267 55

The composition of atherosclerotic plaques is a crucial factor in determining rupture, thrombosis and clinical events. In this study, we analyzed gene expression in coronary plaques from patients with stable or unstable angina using gene arrays. Total RNA was extracted from eight plaques collected by therapeutic directional coronary atherectomy. cDNA probes, generated by amplification, were hybridized to nylon arrays containing 482 genes. Here we report the results for the inflammation, adhesion and hemostasis subsets. Many genes not previously associated with atherosclerosis, such as the lymphocyte adhesion molecule MadCAM, were expressed in the plaques. anova analysis showed higher tissue factor (TF) expression in unstable angina samples. Five genes were expressed at lower levels in unstable angina samples: anticoagulant protein S, cyclooxygenase (COX)-1, interleukin (IL)-7 and chemokines monocyte chemotactic protein (MCP)-1 and -2. Gene arrays provide a new approach to study plaque composition and identify candidate markers of plaque instability.
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PMID:Identification of differentially expressed genes in coronary atherosclerotic plaques from patients with stable or unstable angina by cDNA array analysis. 1287 22

Long-term arsenic exposure is associated with an increased risk of vascular diseases including ischemic heart disease, cerebrovascular disease, and carotid atherosclerosis. The pathogenic mechanisms of arsenic atherogenicity are not completely clear. A fundamental role for inflammation in atherosclerosis and its complications has become appreciated recently. To investigate molecular targets of inflammatory pathway possibly involved in arsenic-associated atherosclerosis, we conducted an exploratory study using cDNA microarray and enzyme-linked immunosorbent assay to identify genes with differential expression in arsenic-exposed yet apparently healthy individuals. As an initial experiment, array hybridization was performed with mRNA isolated from activated lymphocytes of 24 study subjects with low (0-4.32 microg/L), intermediate (4.64-9.00 microg/L), and high (9.60-46.5 microg/L) levels of blood arsenic, with each group comprising eight age-, sex-, and smoking frequency-matched individuals. A total of 708 transcripts of known human genes were analyzed, and 62 transcripts (8.8%) showed significant differences in the intermediate or high-arsenic groups compared with the low-level arsenic group. Among the significantly altered genes, several cytokines and growth factors involving inflammation, including interleukin-1 beta, interleukin-6, chemokine C-C motif ligand 2/monocyte chemotactic protein-1 (CCL2/MCP1), chemokine C-X-C motif ligand 1/growth-related oncogene alpha, chemokine C-X-C motif ligand 2/growth-related oncogene beta, CD14 antigen, and matrix metalloproteinase 1 (interstitial collagenase) were upregulated in persons with increased arsenic exposure. Multivariate analyses on 64 study subjects of varying arsenic exposure levels showed that the association of CCL2/MCP1 plasma protein level with blood arsenic remained significant after adjustment for other risk factors of cardiovascular diseases. The results of this gene expression study indicate that the expression of inflammatory molecules may be increased in human subjects after prolonged exposure to arsenic, which might be a contributory factor to the high risk of atherosclerosis in arseniasis-endemic areas in Taiwan. Further multidisciplinary studies, including molecular epidemiologic investigations, are needed to elucidate the role of arsenic-associated inflammation in the development of atherosclerosis and subsequent cardiovascular disease.
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PMID:Gene expression of inflammatory molecules in circulating lymphocytes from arsenic-exposed human subjects. 1292 51

Atherosclerotic cardiovascular disease is the leading cause of premature death in patients with diabetes. Atherosclerosis is a chronic immune-mediated disease, the initiation, progression, and destabilization of which is driven and regulated by inflammatory cells. One critical event in the initiation of this vascular inflammatory disease is the adhesion of leukocytes to the activated endothelium and their migration into the vessel wall. These processes are mediated by the upregulation of adhesion molecules on endothelial cells (ECs) and an increased expression in the vascular wall of chemotactic factors to leukocytes. Monocyte binding to ECs is increased in diabetes. One major determinant of this alteration could be oxidative stress. Given the free-radical scavenging activity of gliclazide, we determined the ex vivo and in vitro effects of this drug on human monocyte binding to ECs and the molecular mechanisms involved in this effect. Our results demonstrate that short-term administration of gliclazide to patients with type 2 diabetes normalizes the levels of plasma lipid peroxides and monocyte adhesion in these subjects. Gliclazide (10 microg/mL) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to ECs in vitro. The inhibitory effect of this drug on AGE-induced monocyte adhesion involves a reduction in EC adhesion molecule expression and inhibition of nuclear factor kappaB (NF-kappaB) activation. In addition, gliclazide inhibits oxLDL-induced monocyte adhesion to cultured human aortic vascular smooth muscle cells (HASMCs) in vitro and reduces the production of monocyte chemotactic protein-1 (MCP-1) by these cells. Taken collectively, these results show that gliclazide, at concentrations in the therapeutic range, inhibits ex vivo and in vitro monocyte adhesiveness to vascular cells. By doing so, this drug could reduce monocyte recruitment into the vessel wall and thereby contribute to attenuating the sustained inflammatory process that occurs in the atherosclerotic plaque. These findings suggest that treatment of diabetic patients with this drug may prevent or retard the development of vasculopathies associated with diabetes.
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PMID:Benefits of gliclazide in the atherosclerotic process: decrease in monocyte adhesion to endothelial cells. 1293 34

There is growing evidence supporting the importance of inflammation in all stages of atherosclerosis. While both omega-3 polyunsaturated fatty acids (n3PUFA) and the lipid-soluble antioxidant alpha-tocopherol (AT) have been shown to independently have significant anti-inflammatory effects, there is paucity of data examining the effect of n3PUFA alone and in combination with AT on markers of inflammation and monocyte function. Therefore, we tested the effect of n3PUFA alone, all-rac (synthetic) AT alone, and the combination on markers of inflammation and monocyte function. Healthy nonsmoking volunteers were randomly assigned to 1 of 4 groups (n = 20 per group): 1.5 g/d n3PUFA, 800 IU/d AT, 1.5 g n3PUFA + 800 IU/d AT, or placebo in a parallel double-blinded study. Compared to baseline, 12 weeks of supplementation resulted in no changes in plasma lipids regardless of treatment. Plasma AT was significantly increased only in those groups that received AT (P <.0001). Similarly, groups receiving n3PUFA showed a significant increase in plasma docosahexaenoic acid (P <.0001). No significant within- or between-group differences were found for plasma levels of high-sensitivity C-reactive protein (hsCRP). Furthermore, there were no differences in monocyte proinflammatory cytokine release (interleukin [IL]-1beta, tumor necrosis factor [TNF]-alpha and IL-6) after activation with monocyte chemotactic protein-1 (MCP-1). In conclusion, supplementation with n3PUFA and all-rac AT at these doses is not anti-inflammatory.
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PMID:Supplementation with omega3 polyunsaturated fatty acids and all-rac alpha-tocopherol alone and in combination failed to exert an anti-inflammatory effect in human volunteers. 1476 77

It has been widely shown that many plant-derived compounds present significant anti-inflammatory effects. For this reason, they represent potential molecules for the development of new drugs, especially designed for the treatment and/or control of chronic inflammatory states such as rheumatism, asthma, inflammatory bowel diseases, atherosclerosis, etc. This review focuses on the naturally-occurring compounds with anti-inflammatory properties and attempts to correlate their actions with the modulation of cytokines and associated intracellular signalling pathways; it continues the review published in the November, 2003 issue of Planta Medica. Abbreviations. AP-1:activator protein-1 CCR1:chemokine receptor 1 CINC-1:cytokine-induced neutrophil chemoattractant 1 COX:cyclooxygenase EGCG:(-)-epigallocatechin gallate ELAM-1:endothelial-leukocyte adhesion molecule-1 ERK:extracellular signal-regulated kinase GRO:growth-related oncogene HUVEC:human umbilical vein endothelial cells ICAM-1:intercellular adhesion molecule-1 IFN:interferon IL:interleukin iNOS:inducible nitric oxide synthase IRA:the natural interleukin receptor activation JAK:janus kinase JNK:c-Jun NH2-terminal kinase LPS:lipopolysaccharide MAPK:mitogen-activated protein kinases MCP:monocyte chemotactic protein MHC:major histocompatibility complex MIP:macrophage inflammatory protein MMP:matrix metalloproteinases MPO:myeloperoxidase NF-kappaBnuclear factor kappa B NO:nitric oxide PAF:platelet aggregation factor PGEE:prostaglandin PK:protein kinase PMA/TPA:phorbol myristate acetate RANTES:regulated upon activation normal T-cell expressed and secreted TGF-beta:transforming growth factor-beta TNFalpha:tumour necrosis factor VCAM-1:vascular cell adhesion molecule-1
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PMID:Anti-inflammatory compounds of plant origin. Part II. modulation of pro-inflammatory cytokines, chemokines and adhesion molecules. 1499 84

AGI-1067, the monosuccinic acid ester of probucol, is a phenolic antioxidant member of a novel class of agents termed vascular protectants. It has strong antioxidant properties, equipotent to those of probucol, and anti-inflammatory properties. It inhibits gene expression of vascular cell adhesion molecule-1 and monocyte chemotactic protein-1 and has been effective at preventing atherosclerosis in all tested animal models. It also improved luminal dimensions of reference segments in the percutaneous coronary intervention (PCI) vessels in the CART-1 clinical trial, which suggests a direct anti-atherosclerosis effect. Two important trials that test the antioxidant/anti-inflammatory hypothesis are ongoing with AGI-1067: the Canadian Atherosclerosis and Restenosis Trial, which assesses its value for the reduction of both atherosclerosis progression in non-PCI vessels and post-PCI restenosis, and the Aggressive Reduction of Inflammation Stops Events trial, which is evaluating the effects of AGI-1067 on hard cardiovascular outcomes.
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PMID:Vascular protectants for the treatment of atherosclerosis. 1503 Feb 66

In the last decade, the understanding of the molecular mechanisms of regulation of the inflammatory process in chronic inflammatory diseases has moved remarkably forward. Recent evidence in various fields has consistently indicated that T-cells play a key role in initiating and perpetuating inflammation, not only via the production of soluble mediators but also via cell/cell contact interactions with a variety of cell types through membrane receptors and their ligands. Signalling through CD40 and CD40 ligand is a versatile pathway that is potently involved in all these processes. In this article, we review how T-cells become activated by dendritic cells or inflammatory cytokines, and how these T-cells activate, in turn, monocytes/macrophages, endothelial cells, smooth muscle cells and fibroblasts to produce pro-inflammatory cytokines (tumour necrosis factor alpha, interleukin-6), chemokines (interleukin-8, monocyte chemotactic protein-1), tissue factor, the main initiator of the coagulation cascade in vivo, and finally matrix metalloproteinases, responsible for tissue destruction. Moreover, we discuss how CD40 ligand at inflammatory sites stimulates fibroblasts and tissue monocyte/macrophage production of VEGF, leading to angiogenesis, which promotes and maintains the chronic inflammatory process. This cascade of events is discussed in the context of disease initiation/progression, with particular reference to atherosclerosis and rheumatoid arthritis, and to potential novel therapeutic targets for their treatment.
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PMID:T-cell-mediated signalling in immune, inflammatory and angiogenic processes: the cascade of events leading to inflammatory diseases. 1503 40


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