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)

Thrombus formation at the site of atherosclerotic lesions, especially on a ruptured plaque, plays a central role in the "atherothrombosis" hypothesis. An activation of the hemostasis and a disturbed fibrinolysis are known. These alterations are especially marked in patients with acute coronary syndromes. In stable coronary artery disease, fibrinogen is elevated. Furthermore, minor alterations of the contact phase factor VII and consecutively of the thrombin system are detectable depending on the study population. Thrombin generation and activation become marked in patients with unstable angina pectoris or acute myocardial infarction. Possible reasons for this activation are an activation of the contact phase factor XII system and the release of tissue factor both from the ruptured plaque and from stimulated monocytes. The fibrinolytic system is markedly altered already in patients with stable coronary heart disease. Increased levels of tissue-type plasminogen activator and of urokinase-type plasminogen activator/receptor are measurable in atheromas. Tissue-type plasminogen activator mass concentration is systemically elevated already at early stages of atherosclerosis. Especially in patients with increased risk for acute coronary syndromes, the plasminogen activator inhibitor activity is significantly increased. Furthermore, a hypercoagulative state with increased d-dimer levels and plasmin-antiplasmin complexes can be measured. The alterations of hemostasis and especially of fibrinolysis are detectable for prolonged time period and persist much longer than the clinical symptoms of the patients. The increased plasminogen activator inhibitor activity is associated with the metabolic syndrome and constitutes an (in part genetically determined) disturbance in patients with stable or unstable coronary heart disease. However, the large intra- und interobserver as well as diurnal variability of this marker limits its use as a routine measure for risk stratification in patients. Alterations of the hemostasis and disturbances of fibrinolysis are detectable during the chronic as well as the acute phase of atherosclerosis. These changes are best documented for coronary heart disease, whereas less data are available for other manifestations of atherosclerosis. The use of newly developed molecular markers for single reaction steps of pathways instead of global functional tests and of new molecular biological methods did considerably improve the detailed knowledge on the pathomechanisms of the development of atherosclerosis, making the development of targeted therapies, e.g., against receptors possible. Future studies will investigate the quantitative impact of the various activated pathways (cause or reaction) and the effects of interventions on these pathomechanisms in patients with acute coronary syndromes. Studies will have to focus especially on the meaning of polymorphisms, early changes in the development of atherosclerosis and interactions with inflammatory processes.
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PMID:[Blood coagulation and fibrinolysis in arteriosclerosis]. 1041 53

Neovascularization of the atherosclerotic plaque is responsible for its weakening and consequently for the complications of vascular disease. Macrophages are a source of growth factors that can modulate angiogenesis. In this study, we analyzed the effect of oncostatin M (OSM) on angiogenesis, as it could be involved in the development of atherosclerosis. The effect of OSM was compared with those of leukemia inhibitory factor (LIF) and interleukin-6 (IL-6). On human dermal microvasculature endothelial cells (HMEC-1s), OSM (22.5 to 112.5 pmol/L) induced a dose-dependent increase in cell proliferation greater than that induced by the classic angiogenic factors vascular endothelial growth factor (VEGF; 543 pmol/L) and basic fibroblast growth factor (bFGF; 1.1 nmol/L). LIF (19 to 475 pmol/L) induced only a 30% increase in cell proliferation, and IL-6 had no effect. Furthermore, in a modified Boyden-chamber model, OSM, LIF, and IL-6 were chemoattractant for HMEC-1s. In a tridimensional gel of fibrin, OSM increased tube formation and tube length, which were already noticeable by day 3. LIF and IL-6 induced a weaker effect that was only obvious by day 10. The angiogenic effect of OSM was also demonstrated in vivo in a rabbit corneal model: OSM was more potent than LIF, the length of the neovessels being longer with OSM than with LIF, whereas IL-6 was without effect. We tested factors that could be involved in the proliferative effect of OSM on HMEC-1s. OSM induced only a slight increase in the urokinase receptor and a 60% increase in VEGF secretion, whereas it does not modify IL-8 secretion or bFGF levels. The effect of OSM seems to depend on endothelial cell origin and cell species: OSM (up to 112.5 pmol/L) did not induce human umbilical vein endothelial cell proliferation and even had a small inhibitory effect (17%) on calf pulmonary artery endothelial cells. In conclusion, OSM induces an angiogenic effect on capillary endothelial cells, which could be, at least in part, implicated in pathological processes such as atherosclerosis or tumor growth.
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PMID:Oncostatin M induces angiogenesis in vitro and in vivo. 1044 61

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 activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of both tissue-type and urokinase-type plasminogen activators. The balance between plasminogen activators and PAI-1 plays an important role in several physiological and pathophysiological processes such as atherosclerosis or thrombosis. Because these conditions are associated with hypoxia, it was the aim of the present study to investigate the influence of low O(2) tension on the expression of PAI-1 mRNA and protein using primary cultured rat hepatocytes as a model system. We found that PAI-1 mRNA and protein were induced by mild hypoxia (8% O(2)). The hypoxia-dependent PAI-1 mRNA induction was transcriptionally regulated because it was inhibited by actinomycin D (ActD). Luciferase (LUC) reporter gene constructs driven by about 800 bp of the 5'-flanking region of the rat PAI-1 gene were transiently transfected into primary rat hepatocytes; mild hypoxia caused a 3-fold induction, which was mediated by the PAI-1 promoter region -175/-158 containing 2 putative hypoxia response elements (HRE) binding the hypoxia-inducible factor (HIF-1). Mutation of the HRE-1 (-175/-168) or HRE-2 (-165/-158) also abolished the induction by mild hypoxia. Cotransfection of a HIF-1alpha vector and the PAI-1-LUC constructs, as well as gel shift assays, showed that the HRE-2 of the PAI-1 promoter was most critical for induction by hypoxia and HIF-1 binding. Thus, PAI-1 induction by mild hypoxia via a HIF-1 binding HRE in the rat PAI-1 promoter appears to be the mechanism causing the increase in PAI-1 in many clinical conditions associated with O(2) deficiency.
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PMID:Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. 1059 62

In this paper we describe the expression of the tissue plasminogen activator (tPA), urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1) and the uPA receptor (uPAR), in normal and atheromatous human vascular tissue obtained at coronary and peripheral vascular surgery. tPA, uPA, PAI-1 and uPAR antigens were localised by immunohistochemistry. Vessel homogenates were used to quantitate tPA, uPA and PAI-1 antigens as well as uPA and PAI-1 activities using immunoassay and immunoactivity assays, respectively. Quantitative reverse transcription polymerase chain reaction assays (PAI-1 and uPA) were developed and used to quantify PAI-1 and uPA mRNA. In-situ hybridisation (tPA, uPA and PAI-1) was used to localise mRNA. In normal saphenous vein or internal mammary artery, expression of tPA, uPA and PAI expression is associated with endothelium and with intimal or medial smooth muscle cells, but expression is at a low level. uPAR protein was seen on the endothelium of normal saphenous vein or internal mammary artery but absent on the smooth muscle cells. In complex atheroma tPA, uPA, PAI and uPAR proteins were associated with the endothelium, groups of smooth muscle cells (in the intima and around vascular channels, but not with the media), infiltrating mononuclear cells, and also with acellular areas. PAI-1, tPA and uPA mRNA were demonstrated in atheroma in endothelial cells and smooth muscle cells, as well as in areas rich in macrophages. In stenosing saphenous vein grafts there was strikingly increased tPA and uPA (but not PAI-1) expression in neointimal smooth muscle cells and migrating SMC at the intima/media border. A major difference between complex atheroma and either normal vessel or saphenous vein grafts was greatly increased expression of PAI-1 mRNA associated with smooth muscle cells (SMC) in the former. In spite of the greatly increased PAI-1 mRNA expression in atheromatous lesions, the immunoactivity assay showed PAI-1 activity to be low compared to normal internal mammary artery. Our findings would be compatible with previous reports implicating the plasminogen activator/inhibitor system in the initiation and control of matrix remodelling during normal and pathological vessel growth and repair, but also emphasize the complexity of this process in human vessels.
Atherosclerosis 2000 Sep
PMID:Expression of the plasminogen activator system in the human vascular wall. 1099 35

The urokinase-type plasminogen activator (u-PA) has been suggested to play a role in the early initiation and progression of atherosclerosis and coronary artery disease (CAD) (Grenett et aL, 1998). Recently, a common genetic polymorphism in the untranslated region of the u-PA gene was shown to be associated with syptomatic CAD. To study the possible role of this common genetic polymorphism in the u-PA gene, we have developed an automated, PCR-based assay. Automation of the PCR-RFLP genotyping of the BamHI polymorphism of the urokinase gene will support the screening of the large sample sizes required to do the population-based studies necessary to uncover disease susceptibility associations.
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PMID:Automated, PCR-RFLP genotyping of the urokinase gene. 1114 64

The fibrinolytic inhibitor plasminogen activator inhibitor type 1 (PAI-1) plays a role in the development of atherothrombosis and is produced by macrophages that infiltrate the atherosclerotic vessel wall. Because statins are effective in reducing atherosclerosis, we investigated if they modulate the synthesis of PAI-1 in human monocytes/macrophages. To this end, we studied the effect of atorvastatin in different models of monocyte/macrophage differentiation, such as differentiated human promyelocytic cell line HL-60 and human peripheral blood monocyte-derived macrophages. HL-60 cells were differentiated along monocyte lineage by phorbol myristate acetate (PMA) or a mixture of transforming growth factor-beta type 1 (TGF-beta1)/1alpha,25-dihydroxyvitamin D3 (D3). In these conditions, PAI-1 synthesis was strongly induced and atorvastatin upregulated this synthesis, especially during TGF-beta1/D3-induced differentiation. Recombinant human tumor necrosis factor-alpha (TNF-alpha) strongly upregulated PAI-1 synthesis in PMA- or TGF-beta1/D3-differentiated cells, and the potentiating effect of atorvastatin was of the same order as in the absence of TNF-alpha. Mevalonate reversed the enhancing effect of atorvastatin. In mature human monocyte-derived macrophages, atorvastatin, alone or in combination with TNF-alpha, TGF-beta1, or PMA, did not exert any significant effect on PAI-1 synthesis. Basal production of urokinase (uPA), which was below detection limits in HL-60 cells and very low in human monocyte-derived macrophages, was not altered by atorvastatin. These results show that atorvastatin upregulates PAI-1 synthesis during the early stages of monocyte/macrophage differentiation, but has no effect on PAI-1 and uPA synthesis in mature human monocyte-derived macrophages. Atorvastatin did not significantly interact with the upregulating action of TNF-alpha on PAI-1 synthesis during differentiation.
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PMID:Effect of atorvastatin on plasminogen activator inhibitor type-1 synthesis in human monocytes/macrophages. 1139 73

Vascular remodeling, defined as lasting structural changes in the vessel wall in response to hemodynamic stimuli, plays a role in many (patho)physiological processes requiring cell migration and degradation of extracellular matrix (ECM). Two proteolytic systems, the fibrinolytic (plasminogen/plasmin) and matrix metalloproteinase (MMP) systems can degrade most ECM components. The availability of mice models with deficiency of main components of both systems has allowed to study their contribution to vascular remodeling in several biological processes. In mouse models of atherosclerosis, urokinase-mediated plasmin generation plays a role in activation of several macrophage-derived MMPs (MMP-3, -9, -12 and -13), triggering elastolysis and collagenolysis, resulting in media destruction and aneurysm formation. Neointima formation after vascular injury, a process that depends on smooth muscle cell migration, is reduced in mice with plasminogen or urokinase deficiency and enhanced in mice with deficiency of TIMP-1 (type 1 tissue inhibitor of MMPs). Also in allograft transplant arteriosclerosis and in abdominal aortic aneurysm both proteolytic systems contribute to matrix degradation. In a mouse model of myocardial infarction, urokinase deficiency protects totally and MMP-9 deficiency partially against cardiac rupture, but these animals suffer cardiac failure. Thus, the plasminogen/plasmin and MMP systems, in concert, contribute to vascular remodeling in the setting of cardiovascular disease.
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PMID:Plasmin and matrix metalloproteinases in vascular remodeling. 1148 21

Plasminogen activator (PA) inhibitor-1 (PAI-1) has been recognized as a surrogate marker of endothelial dysfunction in diseases associated with impaired angiogenesis, including atherosclerosis, diabetic vasculopathy, and nephropathy. To establish the necessary and sufficient components of the PA system [PAI-1, urokinase-type PA (uPA), or tissue-type PA (tPA), and plasminogen (Plg)] for angiogenesis, we examined angiogenic competence of vascular explant cultures obtained from mice deficient in PAI-1, tPA, uPA, and Plg. To gain insight into the requirement for different matrix-degrading systems during endothelial cell migration across plasmin-degradable basement membranes compared with profibrotic areas containing plasmin-nondegradable collagen, we contrasted vascular sprouting in collagen with Matrigel lattices. PAI-1(-/-) vessels showed an increased capillary sprouting in both collagen and Matrigel. Deficiency of uPA significantly reduced the rate of sprouting, whereas tPA(-/-) vessels showed a profound inhibition of capillary sprouting. The Plg(-/-) vessels failed to sprout, a defect that was restored not only by exogenous Plg, but also by the addition of PAs; a nonproteolytic effect of tPA was observed in Matrigel. Zymography revealed no differences in the activity of metalloproteinase (MMP)-2 and -9 in wild-type and PAI-1(-/-) vessels, but demonstrated reduced MMP-9 activity in all angiogenesis-deficient vessels. In summary, 1) PAI-1 by itself is a modest inhibitor of endothelial sprouting, 2) tPA and Plg are indispensable for angiogenesis in this model, 3) Plg is not the only substrate for PAs, and 4) the activity of MMP-9 is undetectable in explant cultures from tPA and Plg knockout mice.
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PMID:Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis. 1155 72

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


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