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)

Excessive dietary fat and cholesterol exacerbate atherosclerosis. To obtain unbiased insight into the early pathological changes induced by fat feeding in the artery wall, we used high-density microarrays to generate transcriptional profiles of aortic tissue from two groups of atherosclerosis-prone apolipoprotein E-null mice: controls maintained on standard chow and experimental animals exposed short-term to a Western-type diet, a regimen which produced severe hypercholesterolemia without significant development of atheromas. By applying rigorous selection criteria, we identified 311 genes differentially regulated by these dietary conditions. The set of diet-regulated genes exhibited striking functional relationships and represented both novel and known regulatory networks implicated in injury of the artery wall, including cell adhesion genes, histocompatibility antigen and major histocompatibility complex genes, flavin-containing monooxygenases, interferon-regulated genes, small inducible cytokines, collagen and procollagen genes, and complement system components. Further examination of genes identified by this study will provide insights into the molecular mechanisms by which high-fat cholesterol-rich dietary regime initiates pathological alterations in healthy arteries.
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PMID:Transcriptional profiling of early onset diet-induced atherosclerosis in apolipoprotein E-deficient mice. 1576 75

Cathepsin S is one of the major cysteine proteases, and is expressed in the lysosome of antigen presenting cells; primarily dendritic cells, B-cells and macrophages. Cathepsin S is most well known for its critical function in the proteolytic digestion of the invariant chain chaperone molecules, thus controlling antigen presentation to CD4+ T-cells by major histocompatibility complex (MHC) class II molecules or to NK1.1+ T-cells via CD1 molecules. Cathepsin S also appears to participate in direct processing of exogenous antigens for presentation by MHC class II to CD4+ T-cells, or in cross-presentation by MHC class I molecules to CD8+ T-cells. In addition, although direct evidence is still lacking, in its secreted form cathepsin S is implicated in degradation of the extracellular matrix, which may contribute to the pathology of a number of diseases, including arthritis, atherosclerosis and chronic obstructive pulmonary disease. Therefore, inhibition of cathepsin S is a promising target for the development of novel therapeutics for a variety of indications.
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PMID:Cathepsin S inhibitors as novel immunomodulators. 1591 60

Atherosclerosis is a lipid-related chronic inflammatory disease in which immune mechanisms play a pivotal role. The lesions are filled with large numbers of immune cells. During the last decade, dendritic cells have been identified in atherosclerotic plaques and are thought to play an important role in atherogenesis. Dendritic cells express major histocompatibility complex I and II, human leukocyte antigen-DR, CD1a, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and co-stimulatory molecule on their surfaces and this explains their unique ability to activate naive T cells. Factors such as oxidized low-density lipoprotein, hypoxia, nicotine, heat shock proteins, and altered nitric oxide synthase activity of the endothelium, all of which cause endothelial dysfunction, have a significant impact on dendritic cell adherence to endothelium and maturation. Mature dendritic cells are capable of presenting antigens to T cells, and activation of T cells leads to release of cytokines, which play an important role in the progression of disease. Drugs such as statins and diltiazem have been shown to protect endothelial function by inhibition of dendritic cell-endothelial cell interaction, and can be applied to delay the progression of cardiovascular diseases.
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PMID:Role of dendritic cells in atherosclerosis. 1655 30

CD1 molecules are a family of major histocompatibility complex (MHC)-related glycoproteins that present lipid and glycolipid antigens to T cells. Interestingly, it has been demonstrated that CD1d-restricted T cells have a pathogenic role in atherosclerosis. Recent studies suggest an association between the cellular machinery that loads CD1 molecules with glycolipids and several key proteins in lipid metabolism. These proteins include the sphingolipid activator proteins (SAPs), microsomal triglyceride transfer protein (MTP) and apolipoprotein E (apoE). MTP and SAPs seem to be crucial for loading CD1d with lipids in the endoplasmic reticulum and endosomal compartments, respectively, whereas apoE facilitates efficient uptake and delivery of exogenous lipid antigens to CD1d in endosomal compartments. These studies reveal new and unexpected relationships between lipid metabolism and antigen presentation by CD1 molecules. Targeting this pathway of immune activation might have therapeutic potential for the treatment of chronic inflammatory diseases.
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PMID:Lipid metabolism, atherogenesis and CD1-restricted antigen presentation. 1665 Oct 26

Aiming to study the role of human major histocompatibility complex (MHC) region on coronary artery disease (CAD), we enrolled two separate patient materials and controls. First, heart transplantation recipients (n = 276) were divided into three subgroups according to the severity of atherosclerosis. The human leukocyte antigen (HLA)-A-B-DR haplotype and gene frequencies were compared between groups. Second, patients with acute coronary syndrome (ACS) (n = 100) and healthy controls (n = 74) were assessed by nine genetic MHC markers (HLA-A, HLA-B, HLA-DRB1, LTA+253(a/g), LTA+496(C/T), LTA+633(c/g), LTA+724(C/A), C4A and C4B), and the frequencies were compared. In the heart transplantation recipients, HLA-DR1 was strongly associated with CAD [severe vs no evidence, odds ratio (OR) 2.37; 95% confidence interval (CI) 1.33-4.25; P = 0.003]. Similarly, in the patients with ACS, HLA-DRB1*01 was associated with CAD (patients vs controls, OR 2.36; 95% CI 1.25-4.44; P = 0.007). HLA-DRB1*01 was associated with low-density-lipoprotein cholesterol (OR 5.32; 95% CI 1.64-17.26; P = 0.005) and smoking habit (OR 3.13; 95% CI 1.09-9.03; P = 0.035) as risk factors. The strongest protective gene was HLA-B*07 alone (OR 0.46; 95% CI 0.24-0.88; P = 0.02) or together with the haplotype LTA+253a-LTA+633g-C4A3-C4B1 (OR 0.36; 95% CI 0.22-0.57; P = 0.00001). In conclusion, human MHC region harbors genes that protect from and predispose to CAD.
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PMID:Human MHC region harbors both susceptibility and protective haplotypes for coronary artery disease. 1721 7

Apolipoprotein M (apoM), a novel human apolipoprotein recently discovered, predominantly presents in high density lipoprotein (HDL) in plasma, exclusively expressed in liver and in kidney. The present data demonstrated apoM protects against atherosclerosis (AS) primarily via partaking in prebeta-HDL formation and promoting cholesterol efflux to HDL. However, this lipid-metabolism-associated pathway seems unlikely responsible for all atheroprotective effects of apoM. Notably, the human apoM gene is just located in the major histocompatibility complex class III region (MHC-III) on chromosome 6, many genes in this region are related to the immune and inflammatory response. Furthermore, apoM has been documented to link with some inflammatory factors including platelet activating factor (PAF) and leptin. These evidences indicate that apoM may be involved in inflammatory activities in vivo and the potential immuno- and inflam-reactive property of apoM may contribute to the anti-inflammatory function of HDL, as generally acknowledged as an important atheroprotective mechanism of HDL.
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PMID:Apolipoprotein M likely extends its anti-atherogenesis via anti-inflammation. 1721 68

Dendritic cell (DC) maturation may accelerate autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, and may contribute to accelerated atherosclerosis seen in these patients. The immune system responds to both exogenous and endogenous 'dangerous' signals that can induce dendritic cell maturation. We have found that autologous plasma contains danger signals that induce up-regulation of major histocompatibility complex (MHC) class II and co-stimulatory molecules in immature DCs (iDCs). The objective of this study was to determine whether low-density lipoprotein (LDL) and/or oxidized LDL (oxLDL) constitute danger signals, and to assess the effect of exposure to LDL and oxLDL following monocyte differentiation into iDCs in lipoprotein-deficient serum (LPDS). IDCs were generated in the presence of autologous plasma or LPDS. Expression of maturation and migration molecules was evaluated using flow cytometry, and morphology was assessed by light microscopy. Pro- or anti-apoptotic effect was determined using annexin V and propidium iodide binding. Phagocytosis of apoptotic cells was evaluated using autologous plasma or LPDS. LDL and oxLDL were clearly able to slightly up-regulate levels of HLA-DR and co-stimulatory molecule CD86. High oxLDL concentrations (50-100 microg/ml) were associated with expression of additional maturation molecules. Moreover, iDCs that were prepared in LPDS showed partial maturation following exposure to LDL and oxLDL, and improved tolerogenic apoptotic cell uptake. This study suggests that oxLDL, and to some extent LDL, are at least partly responsible for the iDC 'danger' response induced by autologous plasma.
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PMID:'Danger' effect of low-density lipoprotein (LDL) and oxidized LDL on human immature dendritic cells. 1764 66

Acquired immunity disturbances in hemodialysis (HD) patients are many and diverse. They are caused by uremia per se, the HD procedure, chronic renal failure complications, and therapeutic interventions for their treatment. Current data suggest that acquired immunity disturbances in HD patients concern mainly the T-lymphocyte and the antigen-presenting cell (APC). The T-lymphocyte-dependent immune response is deficient, predisposing to infections and inadequate response to vaccinations. In addition, APCs are preactivated, which seems to be responsible for the malnutrition-inflammation-atherosclerosis syndrome, and also affects T-lymphocyte function. At the molecular level it is assumed that the interaction between the APC and the T-lymphocyte is impaired. This disturbance is likely to concern the signal that results from the interaction between the major histocompatibility complex:peptide complex on APC surfaces and T-cell receptors on T-lymphocyte surfaces, or the signal that results from the interaction among the co-receptors of these two cells. The aim of the present review was to collect and classify the available clinical and experimental data in this area. Although many pieces are still missing from the puzzle, a better understanding of the responsible molecular mechanisms, will potentially lead to increased survival and a better quality of life in HD patients.
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PMID:Disturbances of acquired immunity in hemodialysis patients. 1789 51

Acute coronary syndromes (ACS) are characterized by multiple unstable coronary plaques and elevated circulating levels of inflammatory biomarkers. The endothelium of internal mammary arteries (IMA), which are atherosclerosis resistant, is exposed to proinflammatory stimuli as vessels that develop atherosclerosis. Our study investigated the IMA endothelial expression of inflammatory molecules in patients with ACS or chronic stable angina (CSA). IMA demonstrated normal morphology, intact endothelial lining, and strong immunoreactivity for glucose transporter 1. E-selectin expression was observed more frequently in IMA of ACS patiention than CSA patients (ACS 61% vs. CSA 14%, P = 0.01). High fluorescence for major histocompatibility complex (MHC) was significantly more frequent on the luminal endothelium (ACS 66.7% vs. CSA 17.6%, P = 0.001 for class I; and ACS 66.7% vs. CSA 6.2%, P = 0.0003 for class II-DR) and on the vasa vasorum (ACS 92.9% vs. CSA 33.3% and 7.7%, P = 0.0007 and P < 0.0001 for class I and class II-DR, respectively) of ACS patients than CSA patients. ICAM-1, VCAM-1, Toll-like receptor 4, tissue factor, IL-6, inducible nitric oxide synthase, and TNF-alpha expression were not significantly different in ACS and CSA. Circulating C-reactive protein [ACS 4.8 (2.6-7.3) mg/l vs. CSA 1.8 (0.6-3.5) mg/l, P = 0.01] and IL-6 [ACS 4.0 (2.6-5.5) pg/ml vs. CSA 1.7 (1.4-4.0) pg/ml, P = 0.02] were higher in ACS than CSA, without a correlation with IMA inflammation. The higher E-selectin, MHC class I and MHC class II-DR on the endothelium and vasa vasorum of IMA from ACS patients suggests a mild, endothelial inflammatory activation in ACS, which can be unrelated to the presence of atherosclerotic coronary lesions. These findings indicated IMA as active vessels in coronary syndromes.
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PMID:Mild inflammatory activation of mammary arteries in patients with acute coronary syndromes. 1844 Nov 95

The chemokine receptor CCR5 is implicated in the pathogenesis of various inflammatory diseases, such as multiple sclerosis (MS), atherosclerosis, transplant rejection, and autoimmunity. In previous studies, we have shown that MS lesions are characterized by enhanced expression of transcription factors associated with stress responses, ie, IRF-1, NF-kappaB, and CREB-1, which modulate expression of both classes of major histocompatibility complex (MHC) molecules. The expression of MHC-I and MHC-II molecules greatly overlaps with the expression of CCR5 in MS lesions. Therefore, we investigated whether these factors are also involved in the transcriptional regulation of CCR5. Using in vitro assays, we determined that neither IRF-1 nor NF-kappaB is involved in the activation of the CCR5 promoter. This is corroborated by the finding that these factors are not involved in the induction of endogenous CCR5 transcription in various cell types. In contrast, we show that CCR5 expression is regulated by the cAMP/CREB pathway and that interference in this pathway affects endogenous CCR5 transcription. From this, we conclude that the cAMP/CREB pathway is involved in the regulation of CCR5 transcription and that, given the ubiquitous nature of CREB-1 protein expression, additional regulatory mechanisms must contribute to cell type-specific expression of CCR5.
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PMID:CC chemokine receptor 5 gene promoter activation by the cyclic AMP response element binding transcription factor. 1851 6


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