Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In order to investigate processes, such as atherosclerosis and inflammation in vitro, it is necessary to obtain viable and pure endothelial cell cultures from human hearts. To this end, endothelial cells were isolated and cultured from the micro- and macrovasculature of human hearts obtained during heart transplantation. Isolation of capillaries after enzymatic digestion of heart muscle provided a source of microvascular endothelial cells. Contaminating non-endothelial cells were removed by a new technique: paramagnetic beads linked to the lectin ulex europaeus I (UEA-I) were used to select endothelial cells. The resulting cultures contained less than 2% of non-endothelial cells, as judged from immunological staining and fluorescence-activated cell sorting. Both types of endothelial cell displayed typical endothelial properties. They were all positive for factor VIII-related antigen and expressed the endothelial-specific adhesion molecules, CD31 and E-selectin (ELAM-1), after stimulation with cytokines. In addition, they could be labelled with Dil-Ac-LDL, contained angiotensin converting enzyme activity and secreted tissue plasminogen activator, thus demonstrating that typical endothelial functions were preserved in culture.
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PMID:Cultivation and characterization of micro- and macrovascular endothelial cells from the human heart. 829 83

To determine the role of tumor necrosis factor (TNF) in lipopolysaccharide (LPS)-induced inflammation, 12 healthy subjects received an intravenous injection with LPS (2 ng/kg) preceded by infusion of either a recombinant human dimeric TNF receptor type II-IgG fusion protein (TNFR:Fc; 6 mg/m2; n = 6) or vehicle (n = 6) from -30 minutes to directly before LPS injection. LPS elicited a transient increase in plasma TNF activity, peaking after 1.5 hours (219 +/- 42 pg/mL; P < .05). Infusion of TNFR:Fc completely neutralized endogenous TNF activity. LPS administration was associated with an early activation of fibrinolysis (plasma concentrations of tissue-type plasminogen activator, plasminogen activator activity, and plasmin-alpha2-antiplasmin complexes), followed by inhibition (plasma plasminogen activator inhibitor type I), changes that were completely prevented by TNFR:Fc. By contrast, TNFR:Fc did not influence LPS-induced activation of coagulation (plasma levels of prothrombin fragment F1 + 2 and thrombin-antithrombin III complexes). TNFR:Fc strongly inhibited endothelial cell activation (plasma levels of soluble E-selectin), modestly reduced neutrophil responses (neutrophilia and plasma concentrations of elastase-alpha1-antitrypsin complexes and lactoferrin), but did not affect the release of secretory phospholipase A2 or lipopolysaccharide-binding protein (P > .05). Infusion of TNFR:Fc only (without LPS) in another 6 normal subjects did not induce any inflammatory response. These data indicate that TNF is involved in only some inflammatory responses to intravenous LPS in humans.
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PMID:Effect of a recombinant dimeric tumor necrosis factor receptor on inflammatory responses to intravenous endotoxin in normal humans. 916 Jun 78

Human omental microvascular endothelial (HOME) and mesothelial (MESO) cells share many phenotypic properties, but can be characterized from one another based upon a comprehensive panel of endothelial and mesothelial markers. Traditional cell markers such as von-Willebrand factor, DiI-Ac-LDL, and Ulex europaeus I lectin are not sufficient to distinguish between HOME and MESO cells. Furthermore, immunoreactivity to a panel of endothelial cell-specific monoclonal antibodies, including representatives from the known clusters of differentiation (CD), indicate that some of these antigens are coexpressed in HOME and MESO cells. In distinguishing between the two cell types, HOME and not MESO cells express E-selectin, E/P-selectin, P-selectin (CD62), Le-y, and VLA-6 (CDw49f*). Moreover, HOME cells and not MESO cells form tube-like structures when cultured on Matrigel. MESO cells differ from HOME cells based upon (1) the expression of cytokeratins; (2) their rapid proliferation in response to platelet-derived growth factor; and (3) a change from an epitheliod to fibroblast-like morphology in response to tumor necrosis factor and epidermal growth factor. Both HOME and MESO cells express tissue plasminogen activator and plasminogen activator inhibitor, but urokinase activity is only expressed by MESO cells. As there is no one universal endothelial or mesothelial cell marker that can specifically confirm the identity of these cells, it appears necessary to employ a comprehensive panel of cell markers to rule out the possibility of misidentifying a cell culture.
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PMID:Human omental microvascular endothelial and mesothelial cells: characterization of two distinct mesodermally derived epithelial cells. 932 82

The initial step in atherosclerosis is the rapid targeting of monocytes to the sites of inflammation and endothelial injury. Serum levels of intercellular adhesion molecule-1 were found to be increased in ischaemic heart disease patients and polymorphisms in the E-selectin gene were associated with accelerated atherosclerosis in young (age < 40 years) patients, further suggesting a role of inflammation in atherosclerosis. Cholesterol loading in macrophages was found to induce interleukin-8 expression, suggesting an association between foam cell formation and beta 2-integrin-dependent adhesion of leukocytes. Enhanced endothelium-platelet interaction induced by hypercholesterolaemia is mediated by von Willebrand factor, whereas platelet adhesion to subendothelial matrix is mediated by fibulin-fibrinogen complexes. Activated platelets mediate the homing of leukocytes by interaction with the subendothelial matrix under shear stresses that do not allow neutrophil adhesion. They may also contribute to the oxidative modification of LDL, provide a source of lipids for foam cell generation and contribute to smooth muscle cell proliferation. Oxidized LDL induces tissue factor in macrophages that also provide sites for fibrin polymerization and decreases the anticoagulant activity of endothelium by interfering with thrombomodulin expression and inactivating tissue factor pathway inhibitor. Intravascular fibrinolysis induced by tissue-type plasminogen activator or urokinase may contribute to the initiation of atherosclerosis by inducing P-selectin and platelet activating factor as well as to plaque rupture, either directly or indirectly, by activating metalloproteinases. Plasminogen activator inhibitor-1 inhibits smooth muscle cell migration and, in the presence of vitronectin, promotes the clearance of thrombin by LDL receptor-related protein at sites of endothelial injury.
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PMID:Thrombosis and atherosclerosis. 933 57

In health, the vascular endothelium forms a multifunctional interface between the circulating blood and various tissues and organs of the body. It constitutes a selectively permeable barrier for macromolecules, as well as a nonthrombogenic and nonadhesive container that actively maintains the fluidity of blood. It is a metabolically active endocrine organ, serving as the source of multiple factors and mediators that are critical for normal homeostasis. These include vasodilators (nitric oxide, prostacyclin, endothelium-derived hyperpolarizing factor), vasoconstrictors (endothelin-1, thromboxane A2, prostaglandin H2 and components of the renin angiotensin system), various pro- and antithrombotic factors (e.g. tissue factor, platelet activating factor--PAF, von Willebrand factor), fibrinolytic activators and inhibitors (e.g. tissue plasminogen activator, plasminogen activator inhibitor-1), potent arachidonate metabolites (prostanoids), leukocyte adhesion molecules (e.g. E-selectin, P-selectin, intercellular adhesion molecule-1--ICAM-1, vascular cell adhesion molecule-1--VCAM-1), and multiple cytokines with activities of growth stimulators and inhibitors, transforming growth factors, proinflammatory and antiinflammatory mediators, tumour necrosis factors and chemotactic factors (chemokines). Besides these essential activities controlling the cardiovascular system, the endothelial cells represent an important part of the immune system as well. They have a pivotal role in the initiation and development of defensive and damaging inflammatory responses. Therefore endothelium can be considered as being the central equipment for the mutual exchange of life important information between the cardiovascular and immune systems. This in turn is leading to rapid advances in understanding the pathogenesis of some of the most serious and most common diseases, including inflammation, atherosclerosis and hypertension. (Tab. 7, Ref. 89.)
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PMID:[Vascular endothelium as a factor in information transfer between the cardiovascular and immune systems]. 958 73

Twenty-nine patients with clinically defined Takayasu arteritis and 26 healthy control volunteers were recruited by INSSYS investigators from their clinical practices. Patients with Takayasu arteritis were divided into those with clear-cut clinically active or inactive disease based on Birmingham Vasculitis Activity Scores. Multiple serological tests were performed including ESR, C-reactive protein, tissue factor, von Willebrand factor, thrombomodulin, tissue plasminogen activator, ICAM-1, VCAM-1, E-selectin and PECAM-1. No test was reliably able to distinguish between healthy volunteers and patients with active Takayasu arteritis. At present there is no known serological test which can consistently supplant vascular histopathology in determining the activity of Takayasu arteritis.
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PMID:Surrogate markers of disease activity in patients with Takayasu arteritis. A preliminary report from The International Network for the Study of the Systemic Vasculitides (INSSYS). 995 19

During progression of atherosclerosis the overlying endothelial cells alter their expression of some surface molecules. Circulating levels of such molecules may be quantified. We investigated the effect of omega-3 fatty acids (n-3 FA) on the levels of tissue plasminogen activator antigen, von Willebrand factor, and the soluble forms of thrombomodulin, P-selectin, E-selectin, and vascular cell adhesion molecule-1 in 54 patients with coronary heart disease. Twenty-three of the patients had taken 5.1 g/d n-3 FA for 6 months (group I) and 31 were given corn oil as placebo (group II). For another 4 weeks ("the study period") they all got 5.1 g/d of n-3 FA. Compliance was confirmed by demonstration of changes in relevant fatty acids in serum phospholipids. At baseline, significant differences between the groups were found with lower median values of von Willebrand factor (128% versus 147%) and soluble thrombomodulin (24.9 versus 32.5 ng/mL) and higher median values of soluble E-selectin (41.4 versus 35.5 ng/mL) and soluble vascular cell adhesion molecule-1 (573 versus 473 ng/mL) in group I. During the study period differences in changes between the groups were found; tissue plasminogen activator antigen and soluble thrombomodulin decreased (P for difference between the groups 0.001 and 0.015, respectively), whereas soluble E-selectin and soluble vascular cell adhesion molecule-1 increased (P for difference between the groups <0.01 for both) in group II relative to group I. Our results indicate that n-3 FA supplementation decreases hemostatic markers of atherosclerosis, whereas markers of inflammation may be increased. The latter may be the result of lipid peroxidation as a simultaneous decrease of vitamin E and increase in thiobarbituric acid-reactive substances were observed.
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PMID:The effect of supplementation with omega-3 fatty acids on soluble markers of endothelial function in patients with coronary heart disease. 1039 85

The effects of 12 months hormone replacement therapy (HRT) on biochemical markers associated with endothelial function were studied in 98 postmenopausal women with CAD, who were randomized to transdermal HRT or a control group. A significant reduction in the levels of von Willebrand factor in the HRT-group compared to controls was seen after 3 months, maintained after 12 months (p <0.001). Significant reduction in the HRT-group compared to controls was also seen in VCAM-1 after 3 months, sustained after 12 months (p = 0.013 and p = 0.045, respectively), and E-selectin was reduced by about 20% after 3 months on HRT, the reduction being statistically significant after 12 months (p <0.001). Significantly reduced levels of ICAM-1 were also seen after 12 months (p = 0.048). No effects could be observed on tPA-antigen or thrombomodulin. The reduction in procoagulant and proinflammatory markers of endothelial function after long-term transdermal HRT could indicate a beneficial effect on the endothelium and thus a potentially modulating effect on the progression of atherosclerosis in women with CAD.
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PMID:Reduced expression of endothelial cell markers after long-term transdermal hormone replacement therapy in women with coronary artery disease. 1089 53

We compared the effects of oral estradiol (2 mg), transdermal estradiol (50 microg), and placebo on measures of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in 27 postmenopausal women at baseline and after 2 and 12 weeks of treatment. Oral and transdermal estradiol induced similar increases in serum free estradiol concentrations. Oral therapy increased the plasma concentrations of factor VII antigen (FVIIag) and activated factor VII (FVIIa), and the plasma concentration of the prothrombin activation marker prothrombin fragment 1+2 (F1+2). Oral but not transdermal estradiol therapy significantly lowered plasma plasminogen activator inhibitor-1 (PAI-1) antigen and tissue-type plasminogen activator (tPA) antigen concentrations and PAI-1 activity, and increased D-dimer concentrations, suggesting increased fibrinolysis. The concentration of soluble E-selectin decreased and serum C-reactive protein (CRP) increased significantly in the oral but not in the transdermal or placebo groups. In the oral but not in the transdermal or placebo estradiol groups low-density-lipoprotein (LDL) cholesterol, apolipoprotein B and lipoprotein (a) concentrations decreased while high-density-lipoprotein (HDL) cholesterol, apolipoprotein AI and apolipoprotein All concentrations increased significantly. LDL particle size remained unchanged. In summary, oral estradiol increased markers of fibrinolytic activity, decreased serum soluble E-selectin levels and induced potentially antiatherogenic changes in lipids and lipoproteins. In contrast to these beneficial effects, oral estradiol changed markers of coagulation towards hypercoagulability, and increased serum CRP concentrations. Transdermal estradiol or placebo had no effects on any of these parameters. These data demonstrate that oral estradiol does not have uniformly beneficial effects on cardiovascular risk markers and that the oral route of estradiol administration rather than the circulating free estradiol concentration is critical for any changes to be observed.
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PMID:Effects of oral and transdermal estrogen replacement therapy on markers of coagulation, fibrinolysis, inflammation and serum lipids and lipoproteins in postmenopausal women. 1134 95

The aims of this study were to elucidate the factors that contribute to endothelial activation and fibrinolytic abnormalities in patients with poorly controlled type 2 diabetes and to determine whether improved glycemic control reduces endothelial activation. Adhesion molecules [E-selectin, intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1], von Willebrand factor, total nitric oxide (NO), endothelin-1, tissue plasminogen activator, and plasminogen activator inhibitor-1 were measured in 43 type 2 diabetic subjects with hemoglobin A1c of 9.0% or more at baseline (compared with 21 healthy controls) who after 20 wk had been randomized to either improved (IC) or usual (UC) glycemic control. At baseline, type 2 diabetic patients had significant endothelial activation and abnormal fibrinolysis compared with control subjects. Body mass index in the diabetic patients was the only independent predictor of E-selectin (P = 0.007), ICAM-1 (P = 0.01), and NO (P = 0.008) concentrations, but not vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, or tissue plasminogen activator (all P > 0.05). Type 2 diabetic patients with a body mass index of 28 kg/m2 or less had concentrations of E-selectin, ICAM-1, endothelin-1, and NO similar to those in healthy controls. After 20 wk, hemoglobin A1c was significantly lower in IC vs. UC (IC, 8.02 +/- 0.25%; UC, 10.23 +/- 0.23%; P < 0.0001), but there were no significant changes in markers of endothelial activation or indexes of fibrinolysis. Obesity appears to be the most important predictor of endothelial activation in patients with type 2 diabetes. Short-term improvement in glycemic control does not appear to reduce endothelial activation.
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PMID:The influences of obesity and glycemic control on endothelial activation in patients with type 2 diabetes. 1170 27


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