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)

To determine whether thrombin directly modifies mobility of vascular smooth muscle cells (SMC), in Transwell systems (modified Boyden chambers), we exposed SMC to alpha-thrombin. In concentrations as low as 1 NIH U/ml, thrombin induced migration as well as proliferation of SMC. Inhibition of protein synthesis by cycloheximide (2 micrograms/ml) obviated thrombin's chemotactic effect. Neither gamma-thrombin nor D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone (PPACK)-inactivated alpha-thrombin (both used as controls) exerted a chemotactic effect. Concomitant hirudin or antithrombin III plus heparin inhibited chemotaxis by thrombin when added up to 2 h after addition of thrombin. alpha-Thrombin increased SMC synthesis of urokinase receptor (uPAR) and its cell surface expression as shown by metabolic labeling and immunoprecipitation as well as by flow cytometry. Thus alpha-thrombin, in concentrations thought to be present in vivo at sites of vascular injury, can stimulate not only proliferation but also migration of vascular SMC though a mechanism(s) possibly involving synthesis of uPAR, which is known to influence migration in diverse types of cells. Accordingly, both proliferation and migration dependent on thrombin may accelerate atherosclerosis, restenosis, or both after interventions such as angioplasty.
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PMID:Vascular smooth muscle cell migration mediated by thrombin and urokinase receptor. 776 12

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

Atherosclerosis is characterized as a chronic inflammatory-fibroproliferative disease of the vessel wall. The attachment of monocytes and T-lymphocytes to the injured endothelium followed by their migration into the intima is one of the first and most crucial steps in lesion development. The co-localization of CD4+ T-cells and macrophages in the lesion, the abundant expression of HLA Class II molecules and the co-stimulatory molecule CD40 and its ligand (CD40L) indicate a contribution of cell-mediated immunity to atherogenesis. Transgenic mouse models revealed that dependent on the model T- and B-cells may promote lesion progression, monocytes and macrophages are in contrast essential for the development of atherosclerotic lesions. Apart from the local process in the vessel wall, systemic signs of an inflammatory reaction are also associated with lesion development. Thus plasma levels of C-reactive protein and fibrinogen and the white blood cell count are positively correlated to the risk of cardiovascular disease. Recently, an inflammatory phenotype of circulating peripheral blood monocytes could be demonstrated as a specific cellular correlate to lipid and lipoprotein risk factors. Thus the pool size of LPS receptor (CD14)dim and Fc gamma IIIa receptor (CD16a)+ monocytes positively correlates to plasma cholesterol levels, to triglycerides levels and to the apolipoprotein E4 (apo E4) phenotype in contrast to a negative correlation to the high density lipoprotein (HDL) cholesterol concentration. This CD14dim CD16a+ monocytes are further characterized by a high expression of beta 1- and beta 2-integrins, suggesting a higher capacity for attachment at sites of inflammation. A proinflammatory cytokine pattern and an expansion of these cells in other inflammatory diseases are indicating that these cells promote the inflammatory process during atherogenesis. Surface expression of the activation antigen CD45RA on monocytes in correlation to plasma LDL cholesterol and Lp(a) levels further indicates an inflammatory reaction. Regarding the potential mechanisms of the phenotypic changes of peripheral blood monocytes, in a serum free in vitro differentiation model supplemented with M-CSF monocytes from probands which are homozygous for apo E4 showed a significantly higher increase of CD16a expression compared to apo E3/E3 cells indicating that a genetic polymorphism of a single apolipoprotein gene locus may affect monocyte differentiation. The further characterization of the cellular immunology of monocytes and T-lymphocytes in lesion development will provide new specific diagnostic and therapeutic targets in atherogenesis.
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PMID:T-lymphocytes and monocytes in atherogenesis. 964 98

Cell-cell and cell-matrix interactions are key events in morphogenetic processes during development and tissue remodelling. In the vascular system, overexpression of adhesion receptors such as integrins, protease (receptors) or dysregulation of adhesive interactions are directly related to the pathophysiology of cardiovascular diseases (atherosclerosis, restenosis, thrombosis) or angiogenesis-driven tumor progression. Protease cascades such as the plasminogen activation system exhibit a dual role in cell invasion by promoting pericellular proteolysis as well as by regulating cell adhesion and migration in a non-proteolytic fashion. In both these mechanisms, the urokinase receptor (uPAR) plays a central role and may become engaged in complexes with beta1-, beta2-, and beta3-integrins. This article will focus on the molecular and functional interactions between the uPAR system and vascular integrins and discuss implications for cardiovascular function.
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PMID:The dual role of the urokinase receptor system in pericellular proteolysis and cell adhesion: implications for cardiovascular function. 1054 6

Plasminogen can be converted to plasmin either via the tissue-type plasminogen activator (t-PA) or via the urokinase-type plasminogen activator (u-PA)/u-PA receptor (u-PAR) pathway. A dual role for these pathways is now well established: 1) t-PA is involved in fibrin homeostasis and 2) u-PA is primarily involved in cell migration and tissue remodeling. t-PA mediated activation is used for thrombolytic therapy of acute myocardial infarction and some other thromboembolic diseases. The u-PA mediated pathway, in concert with the matrix metalloproteinase (MMP) system, plays a pleiotropic role in arterial neointima formation, atherosclerosis, angiogenesis, tumor growth metastasis, and infarction. However, therapeutic interventions in the u-PA/MMP system remain to be further defined.
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PMID:Ham-Wasserman lecture: role of the plasminogen system in fibrin-homeostasis and tissue remodeling. 1172 75

Vascular cell adhesion and migration, proliferation or differentiation are cellular responses that are induced by haemostatic factors of the urokinase/plasminogen activation complex, but the respective underlying mechanisms are largely undefined. The direct and indirect contributions of the urokinase-type plasminogen activator receptor (uPAR) system in inflammatory processes, as they relate to recruitment of leukocytes, define novel functions and could serve as therapeutic targets for related vasculopathies. The presence of uPAR plays a crucial role in beta2-integrin-mediated adhesion of leukocytes; uPAR also directly mediates leukocyte adhesion to vitronectin, a multifunctional adhesion protein that is associated with the extracellular matrix. The latter process is inhibited by plasminogen activator inhibitor-1. Both beta2-integrin- and uPAR-dependent processes are activated by Zn2+ and are blocked by high-molecular-mass kininogen. Domain 5 of kininogen was identified, in particular, as an anti-adhesive component with a potent anti-inflammatory action in a peritonitis mouse model. In patients with acute myocardial infarction, elevated expression of uPAR on monocytes resulted in their increased adherence to the endothelium, which indicates a possible role of the uPAR system in monocyte recruitment to the infarcted area. Urokinase-type plasminogen activator was identified as a potent mitogen for vascular smooth muscle cells, an observation that was independent of the presence of uPAR and its proteolytic activity. Taken together, these results strongly suggest an essential role for the uPAR system in acute inflammation as well as in chronic degenerative vascular processes such as atherosclerosis. Targeting the uPAR system may allow specific therapeutic intervention in vascular pathologies.
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PMID:Haemostatic factors occupy new territory: the role of the urokinase receptor system and kininogen in inflammation. 1202 45

Activation of the human protease-activated receptor-1 (PAR-1) by thrombin leads to myriad functions essential for maintaining vascular integrity. Upregulation of PAR-1 expression is considered important in atherosclerosis, angiogenesis and tumor metastasis. In vitro analysis of the human PAR-1 promoter function revealed a positive regulatory element between -4.2 and -3.2 kb of the transcription start site. This element was examined in transgenic mice containing either 4.1 or 2.9 kb of the 5' flanking sequence driving a LacZ reporter gene. Only the 4.1 kb PAR-1 transgene was expressed in vivo and only during embryonic development. The transgene expression was observed only in developing arteries and not in veins. Further examination of this putative regulatory sequence identified a novel noncoding RNA (ncR-uPAR:noncoding RNA upstream of the PAR-1) gene at -3.4 kb. The ncR-uPAR upregulated PAR-1-core promoter-driven luciferase activity and mRNA expression in vitro in a Pol II-dependent manner. This noncoding RNA appears to act in trans, albeit locally at the adjacent PAR-1 promoter. These data suggest that an untranslated RNA plays a role in PAR-1 gene expression during embryonic growth.
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PMID:A noncoding RNA regulates human protease-activated receptor-1 gene during embryogenesis. 1208 70

LR11, a member of the LDL receptor family, is highly expressed in vascular smooth muscle cells (SMCs) of the hyperplastic intima, and induces enhanced migration of SMCs in vitro via its upregulation of urokinase-type plasminogen activator receptor (uPAR) expression. In this study, we have delineated the mechanism by which LR11 elevates the expression levels of uPAR in SMCs. Secretion of soluble LR11 is induced in SMCs during the rapidly proliferating phase, and the secreted LR11 induces the migration activities of SMCs. Both the cell-anchored and secreted forms of LR11 have the capacity to bind to and form complexes with uPAR. LR11-overexpressing cells show significantly enhanced uPAR binding, but decreased uPAR internalization. LR11 colocalizes with uPAR on the cell surface and inhibits the LDL receptor-related protein (LRP)-mediated binding and internalization of uPAR. Thus, LR11 mediates the uPAR localization to the plasma membrane. LR11 is highly expressed in the atheromatous plaque areas of apoE knockout mice, particularly in the intimal SMCs at the border between intima and media. The neutralization of LR11 function with anti-LR11 antibody reduced cuff-induced intimal thickness in mice. The novel mechanism of regulation of uPAR localization in SMCs accompanied with enhanced migration activity possibly constitutes an important factor in the process of atherosclerosis and arterial remodeling.
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PMID:LR11, an LDL receptor gene family member, is a novel regulator of smooth muscle cell migration. 1476 53

Proteins in the plasma membrane anchor the cell within its microenvironment and sense changes occurring outside the cell. The anchoring interactions are cell type-specific and may involve adjacent cells or extracellular matrix proteins (ECMPs). In development, wound healing, and in various forms of pathology, including thrombosis and atherosclerosis, the microenvironment of the cell may change rapidly and dramatically. How the cell responds is strongly dependent on the protein composition of its plasma membrane, which we refer to as the plasma membrane proteome. Processes that regulate the plasma membrane proteome may alter cellular response. Low density lipoprotein receptor-related protein-1 (LRP-1) is a member of the LDL receptor family; however, LRP-1 and other less well studied members of this gene family demonstrate multiple activities unrelated to lipid homeostasis. LRP-1 binds and internalizes numerous, structurally diverse ligands, delivering most but not all these ligands to lysosomes for degradation. The intracellular tail of LRP-1 binds signaling adaptor proteins and thus may function in cell signaling. Biological activities of LRP-1 include antigen presentation, phagocytosis, removal of apoptotic cells, and regulation of vascular permeability. This review focuses on an emerging view of LRP-1 activity, in which LRP-1 regulates the protein composition of the plasma membrane and thereby "models" or "landscapes" the cell surface. In some cases, plasma membrane modeling results from the binding to bifunctional ligands or intracellular adaptor proteins, so that LRP-1 is bridged to another plasma membrane protein and the entire complex undergoes endocytosis. Membrane proteins already known to be subject to this form of regulation include urokinase-type plasminogen activator receptor, amyloid precursor protein, tissue factor, and alpha(V)-containing integrins. LRP-1 also controls the plasma membrane proteome by regulating maturation and transport of proteins in the secretory pathway. At the same time, LRP-1 serves as a receptor for specific ECMPs, including fibronectin and thrombospondin. Although ECMP-binding to LRP-1 results in endocytosis and catabolism, these receptor-ligation events also may be coupled, directly or indirectly, to cell-signaling. Based on these novel activities, LRP-1 emerges as a protein capable of modeling the interface of the cell with its microenvironment.
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PMID:Low density lipoprotein receptor-related protein: regulation of the plasma membrane proteome. 1517 90

The role of plasminogen activators in the regulation of key processes of atherosclerosis progression stays unclear. The aim of this study was to evaluate the expression of urokinase plasminogen activator (uPA), its receptor (uPAR) and the plasminogen activator inhibitor type 1 (PAI-1) in human aorta, and to balance them with the stage of atherosclerotic lesion. We have shown that uPA and uPAR in normal aorta are mostly expressed by intimal smooth muscle cells. The expression of these proteins was up-regulated in diseased aorta compared to normal artery. The most part of cells in both fatty streak and fibro-fatty lesion were monocytes/macrophages, and about 60% of these cells expressed uPA and its receptor. PAI-1 was mostly localized on the lumonal part of the aorta and in the extracellular matrix of the intima. We observed a moderate increase of PAI-1 expression in atherosclerotic lesion. Thus, our data indicate participation of plasminogen system in atherogenesis.
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PMID:[Expression of urokinase plasminogen activator, its receptor and plasminogen activator inhibitor type 1 in different types of atherosclerotic lesion in human aorta]. 1534 94


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