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)

Despite primary and secondary prevention, serious cardiovascular events such as unstable angina or myocardial infarction still account for one-third of all deaths worldwide. Therefore, identifying individual patients with vulnerable plaques at high risk for plaque rupture is a central challenge in cardiovascular medicine. Several noninvasive techniques, such as magnetic resonance imaging, multislice computed tomography, and electron beam tomography are currently being tested for their ability to identify such patients by morphological criteria. In contrast, molecular imaging techniques use radiolabeled molecules to detect functional aspects in atherosclerotic plaques by visualizing their biological activity. Based upon the knowledge about the pathophysiology of atherosclerosis, various studies in vitro and in vivo and the first clinical trials have used different tracers for plaque imaging studies, including radioactive-labeled lipoproteins, components of the coagulation system, cytokines, mediators of the metalloproteinase system, cell adhesion receptors, and even whole cells. This review gives an update on the relevant noninvasive plaque imaging approaches using nuclear imaging techniques to detect atherosclerotic vascular lesions.
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PMID:Radionuclide imaging: a molecular key to the atherosclerotic plaque. 1858 28

The E-cadherin/beta-catenin/T-cell factor (Tcf) signaling pathway plays a crucial role in embryogenesis and carcinogenesis and has recently emerged in atherosclerosis. The aim of this work was to investigate whether this signaling pathway is involved in smooth muscle cell proliferation induced by oxidized low-density lipoprotein (LDL). In human aortic smooth muscle cells, mitogenic concentration of mildly oxidized LDL induced the activation of beta-catenin, as assessed by the dissociation of the beta-catenin/cadherin complex, and the concomitant rise of active beta-catenin in the cytosol. The oxidized LDL-induced rise of active beta-catenin required metalloproteinase activation, as well as epidermal growth factor receptor and Src signaling, as assessed by the use of pharmacological inhibitors and cells overexpressing a SrcK-inactive form. The concomitant phosphatidylinositol 3-kinase/Akt activation and glycogen synthase kinase 3-beta phosphorylation induced the inhibition of the proteasomal degradation of beta-catenin. Then active beta-catenin associated with Tcf4 and translocated into the nucleus. This enhanced the expression of the cell cycle activator cyclin D1. This crucial role of beta-catenin in the mitogenic effect of oxidized LDL was confirmed by silencing beta-catenin by specific small interfering RNA that blocked DNA synthesis. Immunohistochemistry staining of stable and disrupted plaques from carotid endarterectomy sections showed a correlation between active beta-catenin and Ki67, a proliferation marker, and a more intense staining in the smooth muscle cell layer surrounding the lipid core of disrupted plaques. In conclusion, the beta-catenin pathway is required for the mitogenic effect of oxidized LDL on human aortic smooth muscle cells. This study highlights the putative important role of the E-cadherin/beta-catenin/Tcf signaling pathway in atherosclerosis.
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PMID:E-cadherin/beta-catenin/T-cell factor pathway is involved in smooth muscle cell proliferation elicited by oxidized low-density lipoprotein. 1870 80

Chlamydia pneumoniae has during recent years been associated with cardiovascular disease and atherosclerosis. Chemokines, leukocyte adhesion proteins and metalloproteinases are significant for chemotaxis and attachment of leukocytes to vessel walls, and for stability of atherosclerotic plaques. To determine the ability of C. pneumoniae to elicit inflammation in a relevant target host cell, we infected human coronary artery endothelial cells (HCAEC) with a clinical isolate of C. pneumoniae. Extracellular release of five chemokines, two adhesion proteins and a metalloproteinase was measured at different time points after infection using a cytometric bead assay and ELISA. Secretion of IL-8, MCP-1, MIG, IP-10 and ICAM-1 was significantly increased 48 h after C. pneumoniae infection of HCAEC in comparison with uninfected controls. Release of RANTES occurred already 6 h after infection. C. pneumoniae did not elicit release of E-selectin or MMP-1. We conclude that C. pneumoniae induces expression of proinflammatory components in HCAEC, which would promote migration of leukocytes towards endothelial cells. This suggests that C. pneumoniae initiates and propagates vascular inflammation in ways that contribute to coronary artery disease.
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PMID:Expression of chemokines and adhesion molecules in human coronary artery endothelial cells infected with Chlamydia (Chlamydophila) pneumoniae. 1913 11

ADAM17 was initially characterized as the TNF Alpha Converting Enzyme (TACE) and, until now, has been the most studied member of the ADAM family. It is a type I transmembrane metalloproteinase involved in the shedding of the extracellular domain of several transmembrane proteins (at least 40) such as cytokines, growth factors, receptors or adhesion molecules. As a consequence, depending on the transmembrane molecule cleaved, one may expect possible opposite effects of ADAM17 activity on inflammation (e.g. TNF and its receptors). The role of ADAM17 in regulating inflammatory cellular processes is clearly demonstrated in cells deficient in active ADAM17 or expressing substrates mutated for the ADAM17 cleavage site. As ADAM17-deficient mice died at birth, mice overexpressing the mutated uncleavable form of some substrates and recently conditional knock-out of ADAM17 are used to approach in vivo the role of this metalloprotease in regulating inflammation. Arguments are provided that ADAM17 plays a role in atherosclerosis, in adipose tissue metabolism, insulin resistance and diabetes. The multitude of substrates cleaved by ADAM17 makes this enzyme an attractive candidate to study its role in inflammation-driven pathologies.
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PMID:[The two sides of ADAM17 in inflammation: implications in atherosclerosis and obesity]. 1915 93

The migration of vascular smooth muscle cells (VSMCs) plays an essential role during the development of atherosclerosis and restenosis. Extensive studies have implicated the importance of extracellular matrix (ECM)-degrading proteinases in VSMC migration. A recently described family of proteinases, a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTs), is capable of degrading vascular ECM proteins. Here, we sought to determine whether ADAMTS-7 is involved in VSMC migration and neointima formation in response to vascular injury. ADAMTS-7 protein accumulated preferentially in neointima of the carotid artery wall after balloon injury. In primary VSMCs, ADAMTS-7 level was enhanced by the proinflammatory cytokine tumor necrosis factor alpha and growth factor platelet-derived growth factor-BB. ADAMTS-7 overexpression greatly accelerated and small interfering RNA knockdown markedly retarded VSMC migration/invasion in vitro. In addition, luminal delivery of ADAMTS-7 adenovirus to carotid arteries exacerbated intimal thickening nearly sixfold 7 days after injury. Conversely, perivascular administration of ADAMTS-7 small interfering RNA but not scramble small interfering RNA to injured arteries attenuated intimal thickening by 50% at 14 days after injury. Furthermore, ADAMTS-7 mediated degradation of the vascular ECM cartilage oligomeric matrix protein (COMP) in injured vessels. Replenishing COMP circumvented the promigratory effect of ADAMTS-7 on VSMCs. Enforced expression of COMP significantly suppressed VSMC migration and neointima formation postinjury, which indicates that ADAMTS-7 facilitated intimal hyperplasia through degradation of inhibitory matrix protein COMP. ADAMTS-7 may therefore serve as a novel therapeutic target for atherosclerosis and postangioplasty restenosis.
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PMID:ADAMTS-7 mediates vascular smooth muscle cell migration and neointima formation in balloon-injured rat arteries. 1916 37

The predisposition to thrombogenesis is increased in essential hypertension, and hypertensive patients are prone to develop more vulnerable atherosclerotic plaques. To evaluate the possible influence of family history of hypertension on some indicators of early atherosclerosis, we studied eighty-five healthy normotensive individuals with (FH+) or without (FH-) family history of essential hypertension by measuring metabolic profile and concentrations of P-selectin, interleukin 6 and matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1. In a subset of individuals, MMP-9 activity was assessed in monocytes by zymography, and TIMP-1 expression by western blot. As compared with FH- individuals, FH+ individuals had significantly higher P-selectin but similar interleukin-6 levels. Although no difference was observed in MMP-2 levels between the two groups, MMP-9 and TIMP-1 were higher in FH+ individuals, who also had higher intracellular MMP-9 levels and TIMP-1 protein expression. P-selectin (r=-0.32; P<0.01), MMP-9 (r=-0.37; P<0.001) and TIMP-1 (r=-0.23; P<0.05) levels were inversely related to high density lipoprotein (HDL) cholesterol. P-selectin was also directly related to serum triglycerides (r=0.30; P<0.01). We conclude that a positive family history of hypertension is associated with an initial increase in markers of inflammation and plaque instability in otherwise healthy young normotensive individuals, likely conveying a predisposition to develop early atherothrombosis.
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PMID:Family history of hypertension, anthropometric parameters and markers of early atherosclerosis in young healthy individuals. 1933 95

The disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family of metalloproteases consists of 19 members. These enzymes play an important role in the turnover of extracellular matrix proteins in various tissues and their altered regulation has been implicated in diseases such as cancer, arthritis and atherosclerosis. Unlike other metalloproteinases, ADAMTS members demonstrate a narrow substrate specificity due to the various exosites located in the C-terminal regions of the enzymes, which influence protein recognition and matrix localization. The tight substrate specificity exhibited by ADAMTS enzymes makes them potentially safe pharmaceutical targets, as selective inhibitors designed for each member will result in the inhibition or cleavage of only a limited number of proteins. With the recent elucidation of crystal structures for ADAMTS-1, -4 and -5, the design of potent and selective small molecule inhibitors is underway and will lead to drug candidates for evaluation in clinical trials in the next 5-10 years.
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PMID:A review of the ADAMTS family, pharmaceutical targets of the future. 1960 37

We studied men with coronary atherosclerosis without acute coronary syndrome and determined typical valuable parameters of inflammatory (tumor necrotic factor, antagonist of receptor to interleukin [IL] 1, IL 6, IL 8, monocytes chemotactic protein 1, endothelial monocytes activating protein II), and destructive (matrix metalloproteinase [MMP] 3, MMP 7, MMP 9, tissue inhibitor of metalloproteinase) processes at consecutive stages of formation of coronary atherosclerotic plaque: "normal intimal tissue --> lipid stain --> early stable plaque --> unstable vulnerable plaque <--> stable plaque with fibrosis", and in 3 types of unstable plaques (lipid type, inflammatory erosive type, necrotic type).
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PMID:[Changes in proinflammatory cytokine and destructive metalloproteinase levels during formation of unstable atherosclerotic plaque]. 1965 94

Atherosclerosis is a vascular inflammatory disease resulting from lipid deposition within vascular wall and changes in structure and function of the vascular wall. Atherosclerosis is accelerated when total and LDL cholesterol are elevated and/or HDL is low. Free radical production is increased in hypercholesterolemia leading to oxidative transformation of both parts of LDL particles, protein and lipid part. Small, dense LDL particles have extreme atherogenic potential; they can be easily oxidized and strongly maintain vascular inflammation. Oxidized LDL particles (oxLDL) support further free radical production. OxLDL are removed by macrophages into sub epithelial space. During that process macrophages produce inflammatory cytokines and induce the production of adhesion molecules, which further cause adherences of new macrophages and further support inflammation. OxLDL also induce sinthesis of endothelial growth factor receptors, which enable transduction of different signals important for: vascular remodeling, cellular migration, mitosis and NF-kappaB activation and increased metalloproteinase activity. HDL particles have an important role in the reverse cholesterol path and protective effects in vascular inflammation and atherogenesis. The ratio of apoprotein AI and AII, amount of CETP, LCAT and paraoxsonase, determine the function of HDL particles. Increased levels of triglycerides in the morning and especially postprandial levels are an independent risk factor for coronary heart disease, and heighten the risk when associated with other lipid disturbances. An increased triglyceride level is associated with the increased PAI I and reduced fibrinolisis. The ratio of total cholesterol/HDL cholesterol, as well as the levels of markers of inflammation such as CRP or IL-6, have great predictive value for the development of ischemic heart disease and cardiovascular diseases.
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PMID:[Vascular inflammation: effect of proatherogenic dyslipidemic trio or quartet]. 1970 14

Accumulating evidence suggests that inflammation plays an essential role in the pathogenesis of atherosclerosis. This recognition has stimulated the evaluation of different inflammatory markers as potential predictors of cardiovascular risk. However, the existing data are limited and controversial. This study was designed to simultaneously measure serum levels of interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with acute ST segment elevation myocardial infarction (STEMI) and to evaluate their ability to predict prognosis. A prospective cohort study was conducted with 263 patients with first STEMI who were admitted to our institute within 6 h of symptoms onset. Clinical data were recorded and serum admission levels of IL-6, sCD40L, MMP-9, and TIMP-1 were measured by sandwich enzyme-linked immunosorbent assay. The patients were then followed prospectively for the occurrence of cardiovascular mortality for 3 years. Follow-up information was available for 228 patients (86.7%) from the 263 STEMI patients; 34 patients died from cardiovascular causes during the 3-year follow-up period. Kaplan-Meier plots demonstrated a significant increase in cardiovascular mortality with increasing IL-6 levels (chi(2) = 14.13, P = 0.0002, by log-rank test). Logistic regression analysis revealed that IL-6 was an independent predictor for cardiovascular mortality. The present study indicates that elevated admission level of IL-6 could provide valuable information for long-term risk stratification in patients with STEMI.
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PMID:Prognostic value of interleukin-6 during a 3-year follow-up in patients with acute ST-segment elevation myocardial infarction. 1978 14


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