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)

The plasminogen activator-plasmin system plays a pivotal role in the delicately regulated process of extracellular matrix remodeling. Recent studies have shown that an imbalance of proteolytic enzymes over specific inhibitors in this system may lead to an aggressive, expanding, and infiltrating cellular phenotype. As cholesteatoma resembles a tumor in many ways, we investigated the pattern of expression for members of the plasminogen activator-plasmin system in 12 human cholesteatomas, using immunohistochemistry. As controls, 3 tympanic membranes and 4 ear canal skin specimens were used. In contrast to the tympanic membranes, all cholesteatoma specimens showed a strong expression of plasminogen at the basal epithelial cell layers. In ear canal skin, only the basal surface of the most basal epithelia stained discretely positive. The urokinase-type plasminogen activator (uPA) could be detected in the basal stratum of the cholesteatoma matrix and in the surrounding granulation tissue, while tissue-type plasminogen activator (tPA) was not detectable at all. Plasminogen activator inhibitor-1 (PAI-1) was expressed in both the granulation tissue and the granular cell layer of the matrix, but not in the basal epithelial cells; PAI-2 showed a pericellular expression pattern in the subbasal and granular cell layers. Neither uPA, tPA, nor the PAIs could be detected in tympanic membrane controls; ear canal skin showed the same staining pattern as cholesteatoma only for PAI-2. Our data demonstrate that there is a clear imbalance in favor of proteolytic activity in the basal epithelial layers of the cholesteatoma matrix, which might at least partly account for the aggressive behavior of this tumorlike lesion. Further, the pattern of expression resembles the pattern described for several epithelial malignancies.
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PMID:Expression pattern of the plasminogen activator-plasmin system in human cholesteatoma. 1008 16

Plasminogen activator inhibitor-1 (PAI-1) rapidly inactivates tissue plasminogen activator (tPA). After initial binding and cleavage of the reactive-centre loop of PAI-1, this complex is believed to undergo a major rearrangement. Using surface plasmon resonance and SDS-PAGE, we have studied the influence of a panel of monoclonal antibodies on the reaction leading to the final covalent complex. On the basis of these data, we suggest the mechanisms for the action of different classes of inhibitory antibodies. We propose that the antibodies which convert PAI-1 into a substrate for tPA do this by means of preventing the conversion of the initial PAI-1/tPA complex into the final complex by sterical intervention. Moreover, the localisation of the binding epitopes on free PAI-1, as well as on the PAI-1/tPA complex, suggests that tPA in the final complex cannot be located near helices E and F, as has previously been proposed.
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PMID:Protein movement during complex-formation between tissue plasminogen activator and plasminogen activator inhibitor-1. 1020 75

Physical exercise activates blood coagulation and enhances fibrinolytic activity. To investigate whether these activations of blood coagulation and fibrinolysis are balanced post-exercise and during the period of recovery, 11 moderately active young men were examined immediately after a standardised cycle ergometer test and during the 24 h period of recovery. Blood samples were obtained at rest, immediately after exercise, and 2, 6 and 24 h after exercise. All post-exercise values were corrected for any change in plasma volume. Exercise induced a significant increase in factor VIII activity and this occurred with a significant shortening of activated partial thromboplastin time. A concomitant enhancement of tissue plasminogen activity resulted in significant increases in tissue plasminogen activity antigen and total fibrin/fibrinogen degradation products, and a significant decrease in tissue plasminogen activator inhibitor-1 activity. Increases in coagulation and fibrinolytic activity changed in parallel during exercise. However, during recovery, while the increase in factor VIII activity post-exercise persisted 2 and 6 h into recovery, fibrinolytic activity demonstrated a sharp fall. It is concluded that whereas the enhanced fibrinolytic activity during exercise appears to counterbalance the increase in blood coagulability, this haemostatic balance is not maintained during recovery. This perturbed blood haemostasis could constitute an enhanced risk for coronary artery thrombosis and may contribute to exercise-related cardiovascular events.
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PMID:Activation and disturbance of blood haemostasis following strenuous physical exercise. 1033 90

Vascular endothelial cells possess antithrombotic properties, which are determined by the balance between plasminogen activators (PAs) and PA inhibitors (PAls). A cell line, TKM-33, has been established and cloned from human umbilical vein endothelial cells, was previously reported to produce a large amount of urokinase-type PA (u-PA) and small amounts of tissue-type plasminogen activator (t-PA) and PA inhibitor-1 (PAI-1). Moreover, TKM-33 expressed the u-PA receptor (u-PAR) which plays an important role in the localization of fibrinolytic activity on cell surface. In the present study, we investigated the localization of u-PA, t-PA, PAI-1 and u-PAR in TKM-33 by using immunofluorescence staining technique. The endothelial cells were strongly stained with anti-PAI-1, anti-u-PA and anti-u-PAR IgGs, and slightly with anti-t-PA IgG. The double immunofluorescence staining with mouse anti-u-PA IgG and rabbit anti-u-PAR IgG followed by rhodamine-conjugated anti-mouse IgG and FITC-conjugated anti-rabbit IgG showed the co-localization of u-PA and u-PAR on the same section of endothelial cells. Although u-PA antigen also existed in the cytoplasm of endothelial cells, u-PAR antigen did not. The treatment of endothelial cells with phorbol-myristate-acetate (PMA) upregulated the expression of u-PA and u-PAR antigens. In this stimulation, u-PAR antigen was detected not only on the surface of the cells but also in the cytoplasm. Thus, the binding of u-PA to u-PAR was confirmed by double immunofluorescence staining.
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PMID:Co-localization of urokinase and its receptor on established human umbilical vein endothelial cell. 1036 70

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.
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PMID:Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. 1050 7

Plasminogen activator inhibitor-1 (PAI-1) is the only functionally labile serpin, as it converts spontaneously into a non-reactive 'latent' conformation. Several studies have suggested an important role for helix F in the functional behavior and stability of the serpins, especially for PAI-1. We constructed a mutant of PAI-1 (PAI-1-delhF) in which residues 127-158 (hF-thFs3A) were deleted. Whereas wild-type PAI-1 (wtPAI-1) exhibits inhibitory properties towards t-PA and u-PA to an extent of 60-80% of the theoretical maximum, PAI-1-delhF did not exert any detectable inhibitory properties, but behaved as a stable substrate. Prolonged incubation at 37 degrees C did not change its functional properties in contrast to wtPAI-1 that under those conditions converts to the latent conformation. In contrast to active wtPAI-1 and other substrate-type PAI-1 mutants, PAI-1-delhF showed a 3000-fold decreased binding to vitronectin. The obtained results clearly show the importance of helix F in the inhibitory activity of PAI-1. The absence of helix F apparently leads to an impaired kinetics of insertion of the reactive site loop upon interaction with its target proteinase resulting in the inability to form a stable covalent complex. Moreover, removal of helix F strongly affects the binding of PAI-1 to vitronectin.
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PMID:The importance of helix F in plasminogen activator inhibitor-1. 1060 63

Variceal bleeding, whose triggering mechanisms are largely unknown, occurs with a circadian rhythmicity, with 2 peaks, one greater, in the evening, and one smaller, in the early morning. We assessed some clotting and hemodynamic parameters, possibly involved in variceal hemorrhage, over a 24-hour period, at 4-hour intervals, in 16 patients with cirrhosis and esophageal varices and in 9 controls. At each time interval, tissue plasminogen activator (tPA) and tPA inhibitor-1 (PAI-1) antigens and activities and total euglobulin fibrinolytic activity were determined and portal-vein flow velocity, volume, and congestion index were measured by duplex-Doppler. Significant circadian rhythms were searched for by least-squares and cosinor methods. tPA activity showed a circadian rhythm in cirrhosis, with a peak of 2.85 times the trough value, calculated at 18:42, and remained over 2.5-fold until shortly after 22:00. Total fibrinolytic activity showed a similar pattern, which was statistically significant also in controls. tPA and PAI antigens also showed significant circadian rhythm both in controls and cirrhotics, with higher values in the morning. Among the portal hemodynamic parameters only the congestion index showed significant rhythmic changes and only in cirrhosis, with the highest values in the late evening, but with limited diurnal excursion (+/- 5.5%). In conclusion, we showed the existence of a circadian rhythm of fibrinolysis in cirrhosis, whose temporal distribution might suggest a role of fibrinolysis in variceal hemorrhage on the basis of the comparison to the known chronorisk of variceal bleeding.
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PMID:Diurnal changes of fibrinolysis in patients with liver cirrhosis and esophageal varices. 1065 57

Regardless of the primary cause, progressive renal deterioration with sclerosis is a hallmark of many renal diseases. Several studies have shown the superiority of angiotensin-converting enzyme inhibitors compared with other antihypertensive agents in providing protection from progressive renal deterioration. Furthermore, animal studies have shown that angiotensin II antagonists in excess of antihypertensive doses can also ameliorate or reverse glomerulosclerosis, leading to the hypothesis that angiotensin II has nonhemodynamic effects that mediate the renoprotective effects shown in these investigations. Although historically angiotensin II has been associated with salt and fluid homeostasis, recent data show that angiotensin II induces cell growth and matrix accumulation in glomerular cells. Plasminogen activator inhibitor-1 has been shown to be the major inhibitor of tissue plasminogen activator and urokinase-like plasminogen activator, with potentially important effects not only on thrombosis/fibrinolysis, but also on matrix degradation because of the proteolytic actions of these substances. Angiotensin II has been shown to influence the actions of plasminogen activator inhibitor-1 and, consequently, its thrombotic and sclerotic effects. Various studies, both in vitro and in vivo, have shown that direct hemodynamic actions, modulation of endothelial injury, and growth factor actions also may be important in the development of sclerosis. These factors can be directly modulated by angiotensin II inhibition. Sclerosis may even be reversed when therapies augment matrix degradation processes, both by directly increasing proteolytic activity and by downregulating inhibitors of matrix degradation. These observations indicate that angiotensin II is important in fibrotic as well as thrombotic renal injuries that lead to progressive renal disease and also in the development of therapies such as specific angiotensin receptor antagonists to prevent or reverse these conditions.
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PMID:The role of angiotensin II and plasminogen activator inhibitor-1 in progressive glomerulosclerosis. 1067 14

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin II type 1 (AT1) receptor blockers share a number of common properties, including their ability to lower blood pressure. However, they can be differentiated based on their individual effects on the renin-angiotensin system, the fibrinolytic system and the actions of bradykinin. They act at different points in the cascade of events that constitute the renin-angiotensin system. In animal models of atherosclerosis, ACE inhibition was associated with a significant reduction in the percentage surface area of lesions, while no similar effect was evident with AT1 receptor blockade. In the fibrinolytic system, both ACE inhibition and AT1 receptor blockade were associated with reduced aldosterone levels, although the effect was greater with ACE inhibition; only ACE inhibition was associated with a significant reduction in plasminogen activation inhibitor-1. By blocking the degradation of bradykinin, ACE inhibitors potentiate the ability of bradykinin to reduce blood pressure and stimulate the release of tissue-type plasminogen activator from the vasculature, an effect not seen with AT1 receptor blockers.
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PMID:Pharmacology of ACE inhibitors versus AT1 blockers. 1090 25

It is known that exercise induces modification in blood haemostasis. It is, however, not known whether alcohol consumption post-exercise influences these modifications during recovery. Eleven moderately active young men were studied immediately after a standardised cycle ergometer test and during the 24-hour period of recovery. Alcohol (0. 7 g/kg body mass) was given 1 hour after exercise on one test occasion, while an equal volume of alcohol-free solution was administered on the other. Exercise induced a significant increase in factor VIII activity with a significant shortening of activated partial thromboplastin time. Parallel increases in tissue plasminogen activity and antigen with a concomitant decrease in tissue plasminogen activator inhibitor-1 activity were also observed after exercise. During recovery, while the increase in factor VIII activity post-exercise persisted in both trials, fibrinolytic activity demonstrated a sharp fall. The elevated factor VIII activity was significantly higher at 5 and 22 hours during the alcohol trial compared with the control. Although no demonstrable effect of alcohol on tissue plasminogen activator activity was present from 1 hour after ingestion onward, tissue plasminogen activator antigen and tissue plasminogen activator inhibitor-1 antigen increased significantly 22 hours following alcohol ingestion. Further comparison between trials revealed a higher plasminogen activator inhibitor-1 activity 5 hours after alcohol ingestion. In conclusion, exercise-induced changes to blood haemostasis are balanced during exercise but not during recovery. Alcohol consumption after physical exercise further perturbs blood haemostasis and could constitute a thrombotic risk.
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PMID:Post-exercise alcohol ingestion perturbs blood haemostasis during recovery. 1097 36


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