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

Unlike coronary thrombolysis, the role of platelet activity in the outcome of local thrombolytic therapy for peripheral ischaemia is not well understood. In the present study ten patients undergoing local pulse spray thrombolysis (PST) with recombinant tissue-type plasminogen activator (rt-PA), six patients undergoing conventional infusion thrombolysis (CT) with rt-PA and another six patients undergoing arteriography with iopamidol were studied. Venous blood samples obtained before and after the procedure were analysed using a flow cytometric technique for detection of platelet activation after labelling platelets with VH10, a monoclonal antibody against P-selectin. In the present study no significant differences were observed in P-selectin expression before and after any of the procedures, except that P-selectin expression following ADP stimulation was reduced in patients who had received conventional thrombolysis. Unexpectedly, we observed relatively greater P-selectin expression, particularly after ADP stimulation, both before and following thrombolysis in ten patients in whom thrombolysis was successful compared with six patients in whom thrombolysis was unsuccessful. ADP-induced P-selectin expression on platelets may therefore be a useful predictor of outcome of peripheral intra-arterial thrombolysis.
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PMID:ADP-induced P-selectin expression on platelets as a predictor of successful thrombolysis. 873 36

S-Nitrosylated tissue plasminogen activator (tPA) is formed by S-nitrosylation of the clinically important agent tPA by nitric oxide, thus conferring nitric oxide donor properties to the molecule. Cats were subjected to 90 min of myocardial ischemia and 270 min of reperfusion and were treated with either tPA or S-nitrosylated tPA 10 min before reperfusion. S-Nitrosylated tPA-treated cats demonstrated marked attenuation of cardiac necrosis after myocardial ischemia/reperfusion, compared with cats receiving only tPA (13 +/- 3% vs. 28 +/- 3%, P < .01). Relaxation of ischemic/reperfused left anterior descending coronary artery rings in response to the endothelium-dependent dilators acetylcholine and A23187 was greater in the S-nitrosylated tPA-treated group, compared with the cats receiving only tPA, indicating that coronary vascular endothelial function was preserved by S-nitrosylated tPA. S-Nitrosylated tPA also resulted in markedly reduced adherence of neutrophils to the coronary vascular endothelium, compared with nonnitrosylated tPA (P < .01). Immunohistochemical localization of P-selectin in the ischemic region was also significantly reduced by S-nitrosylated tPA, compared with the control group (P < .01). These data indicate that S-nitrosylated tPA is a cardioprotective agent, likely exerting its effect by site-specific nitric oxide donation resulting in inhibition of neutrophil-endothelium interaction via a P-selectin-dependent mechanism.
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PMID:S-nitrosylated tissue-type plasminogen activator protects against myocardial ischemia/reperfusion injury in cats: role of the endothelium. 896 38

To investigate whether there are differences in haematology and coagulation indices in arterial and venous plasma, and whether those changes related to damage to the endothelium in atherosclerosis, we obtained blood samples from 22 subjects undergoing diagnostic angiography. There were no differences in any of the 15 routine haematological indices measured. There were no differences in prothrombin time, activated partial thromboplastin time, fibrinogen, tissue plasminogen activator, D-dimer, leucocyte elastase, soluble P-selectin or von Willebrand factor. In venous samples, von Willebrand factor was lower in serum than in plasma (p < 0.0001). Levels of the tissue plasminogen activator/plasminogen activator inhibitor-1 (tPA/PAI-1) complex were markedly higher in arterial blood than in venous blood (p = 0.004) and plasma viscosity was higher in venous blood (p = 0.0014). Consequently, with the exception of viscosity and the tPA/PAI complex, we can find no differences in arterial blood compared to venous blood which can contribute to the debate regarding the mechanism of damage to arterial endothelial cells but the relative protection of venous endothelial cells from injury in atherosclerosis.
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PMID:Haematology and coagulation indices in paired samples of arterial and venous blood from patients with arterial disease. 911 85

In previous studies we have shown that, after stimulation by a receptor ligand such as thrombin, tissue-type plasminogen activator (tPA) and von Willebrand factor (vWf) will be acutely released from human umbilical vein endothelial cells (HUVEC). However, the mechanisms involved in the secretion of these two proteins differ in some respects, suggesting that the two proteins may be stored in different secretory granules. By density gradient centrifugation of rat lung homogenates, a particle was identified that contained nearly all tPA activity and antigen. This particle had an average density of 1.11-1.12 g/ml, both in Nycodenz density gradients and in sucrose density gradients. A similar density distribution of tPA was found for a rat endothelial cell line and for HUVEC. After thrombin stimulation of HUVEC to induce tPA secretion, the amount of tPA present in high-density fractions decreased, concomitant with the release of tPA into the culture medium and a shift in the density distribution of P-selectin. vWf, known to be stored in Weibel-Palade bodies, showed an identical distribution to tPA in Nycodenz gradients. In contrast, the distribution in sucrose gradients of vWf from both rat and human lung was very different from that of tPA, suggesting that tPA and vWf were not present in the same particle. Using double-immunofluorescence staining of HUVEC, tPA- and vWf-containing particles showed a different distribution by confocal microscopy. The distribution of tPA also differed from the distribution of tissue factor pathway inhibitor, endothelin-1, and caveolin. By immunoelectronmicroscopy, immunoreactive tPA could be demonstrated in small vesicles morphologically different from the larger Weibel-Palade bodies. It is concluded that tPA in endothelial cells is stored in a not-previously-described, small and dense (d = 1.11-1.12 g/ml) vesicle, which is different from a Weibel-Palade body.
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PMID:An endothelial storage granule for tissue-type plasminogen activator. 931 43

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

Women with premature menopause are at high risk for vascular compications associated with thrombogenesis and atherogenesis. The use of hormone-replacement therapy (HRT), however, may protect against these complications. Hemostatic abnormalities and endothelial function are closely related to the processes of thrombogenesis and atherogenesis. The purpose of the study was to evaluate the effects of premature menopause on markers of hemostasis, platelet function, and endothelial function and the effects of starting HRT. This is a prospective longitudinal study of premenopausal women undergoing surgical menopause in whom estrogen HRT is started. We measured sequential changes in plasma levels of the hemostatic factors (fibrinogen, fibrin D-dimer, and plasminogen activiator inhibitor [PAI]), markers of platelet function (soluble leukocyte adhesion molecule P-selectin) and endothelial function (von Willebrand factor [vWf], soluble thrombomodulin [sTM], and tissue plasminogen activator [TPA]), and serum lipid levels, including lipoprotein A. Twenty-seven premenopausal women (mean age 43.6 +/- 6.5 years) undergoing hysterectomy and bilateral salpingo-oophrectomy were studied. In the postsurgical menopausal state (visit 2), there was a significant elevation in sTM levels (paired Wilcoxon test, p = 0.008). There was also a trend toward higher median soluble P-selectin, PAI, and mean TPA levels and lower vWf levels. After 6 weeks of HRT (visit 3), there was a significant reduction in mean vWf (paired Wilcoxon test, p = 0.0026), sTM (p = 0.039), and TPA levels (p = 0.02) compared with premenopausal levels. There were no significant changes in plasma fibrinogen, fibrin D-dimer, and PAI levels at visit 2 or visit 3 compared with premenopausal levels. There was a significant increase in serum lipoprotein A (paired Wilcoxon test, p = 0.008), cholesterol, and triglyceride levels after surgical menopause (paired t test, p < 0.01). Lipoprotein A and cholesterol levels after HRT (visit 3) were not significantly different from prehysterectomy levels, although triglyceride levels were increased further. HRT results in a significant reduction in vWf, sTM, and TPA levels, suggesting beneficial effects on endothelial function and atherogenesis. Although there was a significant increase in serum lipoprotein A and cholesterol levels after surgical menopause, lipoprotein A and cholesterol levels after HRT were not significantly different from presurgery levels. These observations are consistent with the beneficial effects of HRT in cardiovascular hemodynamics and cardiovascular disease.
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PMID:Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: implications for prevention of atherosclerosis. 935 46

The mechanisms that underlie reocclusion during thrombolytic therapy have not yet been clarified. The purpose of this study was to investigate the activating effects of tissue-type plasminogen activator and urokinase and the inhibitory effects of acetylsalicylic acid by measuring platelet surface P-selectin as a marker of platelet activation. After addition of urokinase (final concentration 192 U/ml, 1920 U/ml, or 19,200 U/ml) or tissue-type plasminogen activator (final concentration 120 U/ml, 1200 U/ml, or 12,000 U/ml) to platelet-rich plasma from 12 healthy persons, platelet surface P-selectin expression was measured by means of flow cytometry with an anti-CD62 monoclonal antibody. The presence of urokinase and tissue-type plasminogen activator increased platelet surface P-selectin expression in a concentration-dependent manner. In the next step, either 160 mg/day (n = 6) or 660 mg/day (n = 6) acetylsalicylic acid was administered to the 12 healthy persons, and venous blood samples were collected after 7 days of treatment. Platelet surface P-selectin expression was measured with the method used earlier and after addition of tissue-type plasminogen activator or urokinase. Although the effect of acetylsalicylic acid at 160 mg/day on P-selectin expression was minimal, a dose of 660 mg/day suppressed platelet P-selectin expression and inhibited the platelet activating effects of tissue-type plasminogen activator and urokinase in a statistically significant way. Platelets were activated by tissue-type plasminogen activator or urokinase, and this platelet activation was suppressed with administration of acetylsalicylic acid at 660 mg/day.
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PMID:Human platelet activation by thrombolytic agents: effects of tissue-type plasminogen activator and urokinase on platelet surface P-selectin expression. 948 75

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

Herpes simplex virus type 1 and cytomegalovirus alter the phenotype of the endothelium in vitro from anticoagulant to procoagulant, thereby promoting the adherence of neutrophils and platelets to the endothelium. Virus infection of the endothelium induces the expression of viral glycoproteins and adhesion molecules, which promote neutrophil and monocyte adhesion. Herpes simplex infection of the endothelium promotes prothrombinase assembly, allowing more efficient thrombin generation. Excess thrombin generation causes translocation of P-selectin. Viral infection also induces the procoagulant molecule, tissue factor, in endothelial cells. These enhanced procoagulant effects are associated with the loss of anticoagulants, including thrombomodulin, prostacyclin and tissue plasminogen activator. These studies support the speculation that virus infection in vivo promotes vascular injury and thrombosis, which may contribute to disease states such as atherosclerosis.
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PMID:Effects of viral activation of the vessel wall on inflammation and thrombosis. 966 64


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