Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.7 (plasmin)
9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The serine proteinases, tissue-type (tPA) and urokinase (uPA) plasminogen activator, are implicated in the ovulatory processes via their ability to convert plasminogen to its active form, plasmin. One mechanism for regulation of plasmin-directed ovarian extracellular matrix remodelling during follicle rupture and corpus luteum formation is through inhibition of plasminogen activation by the plasminogen activator inhibitors (PAI-1 and PAI-2). The effect of the preovulatory gonadotrophin surge on the temporal and spatial regulation of expression of PAI-1 and PAI-2 mRNA and PAI activity in preovulatory bovine follicles and new corpora lutea collected at 0, 6, 12, 18, 24 and 48 h after a GnRH-induced gonadotrophin surge was examined. Both PAI-1 and PAI-2 mRNAs were upregulated markedly after the gonadotrophin surge, with the highest expression observed in follicles collected at about the time of ovulation (24 h) and in corpora lutea (48 h). PAI-1 mRNA was localized primarily to the thecal layer of preovulatory follicles. In contrast, PAI-2 mRNA was localized specifically to the granulosa cell layer. Significant PAI activity was detected in follicle extracts, but temporal or spatial differences in PAI activity were not detected in response to the gonadotrophin surge. These results indicate that PAI-1 and PAI-2 mRNAs are upregulated in preovulatory bovine follicles after the gonadotrophin surge in a cell-specific way. Regulation of PAI-1 and PAI-2 may help to control plasminogen activator activity associated with ovulation and early corpus luteum formation.
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PMID:Gonadotrophin surge-induced upregulation of mRNA for plasminogen activator inhibitors 1 and 2 within bovine periovulatory follicular and luteal tissue. 1200 99

Hemostatic abnormalities in 26 patients following bone marrow transplantation (BMT) were examined. In the event-free survival group, the plasma levels of antithrombin (AT) and protein C (PC) were significantly decreased 1 and 2 weeks after BMT, and the plasma levels of thrombomodulin (TM) and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (tPA-PAI-I complex) were significantly increased from 4 weeks to 13 weeks after BMT. Excepting AT, there was no significant difference in hemostatic parameters before BMT among the event-free survival, 6-month survival, and death within 6 months groups. On day 0 following BMT, only plasma AT levels were significantly lower in the 6-month survival group than in the death within 6 months group. From 1 to 3 weeks after BMT, plasma levels of AT or PC were significantly lower in the death within 6 months group than in the 6-month survival group. From 1 to 5 weeks after BMT, the plasma levels of TM and tissue type plasminogen activator-plasminogen activator inhibitor-I complex (tPA-PAI-I complex) were significantly higher in the 6-month survival group than in the death within 6 months group. From 1 to 13 weeks after BMT, the plasma levels of D-dimer or soluble fibrin monomer (SFM) were significantly higher in the death within 6 months group than in the 6-month survival group. There was no remarkable difference in plasma levels of thrombin-antithrombin comlex or plasmin-plasmin inhibitor complex following BMT between these groups of patients. These findings suggest that the decrease in the plasma AT or PC level reflects early occurrence of complications of prognostic significance and that the increase in vascular endothelial cell markers such as plasma levels of TM or tPA-PAI-I complex reflects occurrence of complications during the middle course of BMT. Plasma levels of D-dimer and SFM may be useful markers for predicting complications associated with poor prognosis after BMT.
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PMID:Hemostatic abnormalities following bone marrow transplantation. 1212 Oct 52

The best known function of the fibrinolytic system is its ability to dissolve blood clots. The key enzyme of fibrinolysis, plasmin, is formed by conversion from plasminogen through the action of activators, the most important of which is tissue type plasminogen activator (tPA). Low levels of tPA or excessive levels of plasminogen activator inhibitor-I (PAI-I) cause hypofibrinolysis, causally related to the development of atherosclerosis and associated thrombotic complications, as well as with the development of venous and arterial thrombosis. A chronic decrease in renal function leads to hypofibrinolysis due primarily to low levels of tPA. Hypofibrinolysis is present both in patients treated by long-term hemodialysis and by peritoneal dialysis. The hemodialysis procedure acutely raises the plasma levels of tPA, primarily as a result of the bioincompatibility of materials in the extracorporeal circuit. In peritoneal dialysis, dialysis solution dwell time is associated with an increase in PAI-I levels in the abdominal cavity. Fibrinolysis defects occur also in renal transplant recipients. In transplant patients, the main abnormality is also hypofibrinolysis which, however, unlike the situation with the other methods of renal replacement therapy, is secondary to a rise in PAI-I. A role in the increase of the plasma levels of PAI-I in transplant patients is played by steroid- and cyclosporine-based immunosuppression, most likely by metabolic disorders such as insulin resistance or dyslipoproteinemia, and by genetic factors. Animal experiments with chronic rejection have shown abnormalities in local fibrinolysis in the graft, particularly increased PAI-I expression. Fibrinolysis defects may contribute to an early and frequent development of atherosclerosis in patients with chronic renal failure, to chronic dysfunction of the renal transplant, or to peritoneal fibrosis and peritoneal catheter obstruction in patients on peritoneal dialysis. The exact role of hypofibrinolysis in the development of these complications, and the potential for modulating it, warrant further research.
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PMID:Fibrinolysis in chronic renal failure, dialysis and renal transplantation. 1222 2

We measured the plasma level of fibrinogen in 560 patients with disseminated intravascular coagulation (DIC) and evaluated its relationship with outcome and with other hemostatic markers. Forty-seven percent of patients had >200 mg/dL of plasma fibrinogen and 24% had <100 mg/dl of plasma fibrinogen, suggesting that plasma fibrinogen level is not a sensitive marker for DIC. In our analysis of outcome and plasma fibrinogen levels, the rate of death was high in leukemia/lymphoma patients with high fibrinogen concentration, but no significant difference in outcome was observed in relation to plasma fibrinogen concentration in non-leukemia/lymphoma patients with DIC. Among patients with leukemia/lymphoma, the frequency of organ failure was markedly high in patients with high plasma levels of fibrinogen. Among patients without leukemia/lymphoma, the frequency of organ failure increased concomitantly with the increase in plasma fibrinogen levels. The international normalized ratio was significantly increased in leukemia/lymphoma patients with low fibrinogen. FDP levels were slightly increased in patients with low fibrinogen. Platelet count was significantly low in patients without leukemia/lymphoma with high fibrinogen. DIC score increased concomitantly with the reduction in plasma fibrinogen levels. Plasma levels of thrombomodulin and tissue factor were significantly high in patients with high fibrinogen levels. Plasma levels of antiplasmin and plasminogen were significantly decreased in patients with low fibrinogen. Plasma levels of plasmin plasmin-inhibitor complex and tissue type plasminogen activator/plasminogen activator inhibitor-1 complex (PAI-I) were significantly higher in patients with low fibrinogen than in those with high fibrinogen. Plasma levels of PAI-I and IL-6 were significantly higher in patients with high fibrinogen than in those with low fibrinogen. Patients with high fibrinogen levels showed less activation of secondary fibrinolysis, which might explain the occurrence of organ failure and poor outcome.
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PMID:High plasma fibrinogen level is associated with poor clinical outcome in DIC patients. 1250 60

During normal pregnancy the hemostatic balance changes in the direction of hypercoagulability, thus decreasing bleeding complications in connection with delivery. The most important initial factor for acute hemostasis at delivery is, however, uterine muscle contractions, which interrupt blood flow. Global tests such as Sonoclot signature, the Thromboelastogram, and a new method analyzing overall plasma hemostasis, all show changes representative of hypercoagulability during pregnancy. Increased endogenous thrombin generation, acquired activated protein C resistance, slightly decreased activated partial thromboplastin time (aPTT) and increased prothrombin complex level (PT) measured as international normalized ratio (INR) of less than 0.9 have been reported as well. In normal pregnancy, the platelet count is within normal range except during the third trimester when benign gestational thrombocytopenia, 80 to 150 x 10 9/L, can be observed. Platelet turnover is usually normal. Activation of platelets and release of beta-thromboglobulin and platelet factor 4 are reported. The bleeding time is unchanged during normal pregnancy. Most blood coagulation factors and fibrinogen increase during pregnancy. Factor (F) XI is the only blood coagulation factor that decreases. Blood coagulation inhibitors are mainly unchanged but the level of free protein S decreases markedly and the level of tissue factor pathway inhibitor increases. Thrombomodulin levels increase during pregnancy. Fibrinolytic capacity is diminished during pregnancy, mainly because of markedly increased levels of plasminogen activator inhibitor-1 (PAI-1) from endothelial cells and plasminogen activator inhibitor-2 (PAI-2) from the placenta. Thrombin-activated fibrinolysis inhibitor is reported to be unaffected. The total hemostatic balance has been studied by analyses of prothrombin fragment 1+2, thrombin-antithrombin complex, fibrinopeptide A, soluble fibrin, D-dimer, and plasmin-antiplasmin complex. There is activation of blood coagulation and a simultaneous increase in fibrinolysis without signs of organ dysfunction during normal pregnancy. These changes increase as pregnancy progresses. During delivery, there is consumption of platelets and blood coagulation factors, including fibrinogen. Fibrinolysis improves and increases fast following childbirth and expulsion of the placenta, resulting in increased D-dimer levels. These changes are self-limiting at normal delivery. The hemostatic changes, noted during pregnancy, normalize after delivery within 4 to 6 weeks. Platelet count and free protein S, however, can be abnormal longer. Hemostasis should not be tested earlier than 3 months following delivery and after terminating lactation to rule out influences of pregnancy. PAI-1 and PAI-2 levels decrease fast postpartum, but PAI 2 has been detected up to 8 weeks postpartum. alpha 2 -antiplasmin, urokinase, and kallikrein inhibitor levels have been reported to be increased 6 weeks postpartum.
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PMID:Hemostasis during normal pregnancy and puerperium. 1270 15

In fibrotic renal disease, elevated TGF-beta and angiotensin II lead to increased plasminogen activator inhibitor type 1 (PAI-1). PAI-1 appears to reduce glomerular mesangial matrix turnover by inhibiting plasminogen activators, thereby decreasing plasmin generation and plasmin-mediated matrix degradation. We hypothesized that therapy with a mutant human PAI-1 (PAI-1R) that binds to matrix vitronectin but does not inhibit plasminogen activators, would enhance plasmin generation, increase matrix turnover, and decrease matrix accumulation in experimental glomerulonephritis. Three experimental groups included normal, untreated disease control, and PAI-1R-treated nephritic rats. Plasmin generation by isolated day 3 glomeruli was dramatically decreased by 69%, a decrease that was reversed 43% (P < 0.02) by in vivo PAI-1R treatment. At day 6, animals treated with PAI-1R showed significant reductions in proteinuria (48%, P < 0.02), glomerular staining for periodic acid-Schiff positive material (33%, P < 0.02), collagen I (28%, P < 0.01), collagen III (34%, P < 0.01), fibronectin (48%, P < 0.01), and laminin (41%, P < 0.01), and in collagen I (P < 0.01) and fibronectin mRNA levels (P < 0.02). Treatment did not alter overexpression of TGF-beta1 and PAI-1 mRNAs, although TGF-beta1 protein was significantly reduced. These observations strongly support our hypothesis that PAI-1R reduces glomerulosclerosis by competing with endogenous PAI-1, restoring plasmin generation, inhibiting inflammatory cell infiltration, decreasing local TGF-beta1 concentration, and reducing matrix accumulation.
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PMID:A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. 1289

During recent years it has become increasingly recognized that the plasmin activation system is involved in the development of atherosclerosis. In this paper, we have studied the contribution of the plasminogen activation system in the development of atherosclerosis by cross-breeding apoE3-Leiden mice, which have a human-like lipid profile, with mice deficient in PAI-1 (plasminogen-activator inhibitor-1), u-PA (urokinase plasminogen activator), and t-PA (tissue plasminogen activator). Genetic compound offspring was used to evaluate the progression of atherosclerotic lesions after they were fed a variant atherogenic diet for 12 weeks. Lesion area of plaques in the aortic valve was not significantly different in apoE3-Leiden:PAI -/- and apoE3-Leiden:u-PA -/- mice as compared to apoE3-Leiden mice. In contrast, a significant 70% reduction of the lesion area was observed in apoE3-Leiden:t-PA -/- mice as compared to control group apoE3-Leiden mice. In addition the early, regular fatty streaks and mild plaques increased in apoE3-Leiden:t-PA -/- mice, whereas the severe plaques (type IV and V) decreased in these animals. A lower deposition of collagen was observed in the atherosclerotic lesions of apoE3-Leiden:t-PA -/- mice as compared with apoE3-Leiden mice. Our results indicate for the first time that t-PA deficiency delayed the atherosclerotic process in this mouse model.
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PMID:Genetic deletion of tissue-type plasminogen activator (t-PA) in APOE3-Leiden mice reduces progression of cholesterol-induced atherosclerosis. 1451 93

Mice deficient in the plasminogen activator inhibitor-1 gene (PAI-1-/- mice) are relatively protected from developing pulmonary fibrosis from bleomycin administration. We hypothesized that one of the protective mechanisms may be the ability of the plasminogen system to enhance hepatocyte growth factor (HGF) effects, which have been reported to be anti-fibrotic in the lung. HGF is known to be sequestered in tissues by binding to extracellular matrix components. Following bleomycin administration, we found that HGF protein levels were higher in bronchoalveolar lavage fluid from PAI-1-/- mice compared to wild-type (PAI-1+/+) mice. This increase could be suppressed by administering tranexamic acid, which inhibits plasmin activity. Conversely, intratracheal instillation of urokinase into bleomycin-injured PAI-1+/+ mice to activate plasminogen caused a significant increase in HGF within bronchoalveolar lavage and caused less collagen accumulation in the lungs. Administration of an anti-HGF neutralizing antibody markedly increased collagen accumulation in the lungs of bleomycin-injured PAI-1-/- mice. These results support the hypothesis that increasing the availability of HGF, possibly by enhancing its release from extracellular matrix by a plasmin-dependent mechanism, is an important means by which activation of the plasminogen system can limit pulmonary fibrosis.
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PMID:The plasminogen activation system reduces fibrosis in the lung by a hepatocyte growth factor-dependent mechanism. 1498 62

Plasminogen activator inhibitor-I (PAI-I) is an important component of the plasminogen/plasmin system as it is the main inhibitor of tissue-type and urokinase-type plasminogen activator. Consequently, PAI-I plays an important role in cardiovascular diseases (mainly through inhibition of t-PA), and in cell migration and tumor development (mainly through inhibition of u-PA and interaction with vitronectin). As a member of the serpin superfamily, PAI-I shares important structural properties with other serpins. However, PAI-I also exhibits unique conformational and functional properties. The current review provides an overview of the knowledge on PAI-I gathered since its discovery two decades ago. We discuss (a) its structural properties of the protein and their subsequent relation to functional activities, (b) its role in a wide variety of (patho)physiological processes and (c) a number of strategies to interfere with its functional properties eventually aiming at pharmacological modulation of this risk factor.
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PMID:The structural basis for the pathophysiological relevance of PAI-I in cardiovascular diseases and the development of potential PAI-I inhibitors. 1498 17

Plasminogen activator inhibitor type-1 (PAI-1) is considered one of the key regulators of tumor invasion, metastasis, as well as cancer-related angiogenesis. The literature suggests that PAI-1 plays a dual role in these processes because it inhibits plasmin-originated proteolysis and binds to vitronectin or integrins. Stimulation or inhibition of angiogenesis largely depends on which of these elements PAI-1 interacts. Wild PAI-1 converts quickly into its latent, inactive form and loses its anti-proteolytic activity, but still binds to vitronectin and integrins. Thus we constructed PAI-1s with extended half-life to prolong their anti-proteolytic activity. We have analyzed the effects of sprout formation inhibition by PAI-1s on two functionally different endothelial cell (EC) systems, human umbilical vein endothelial cells (HUVEC), expressing moderate amounts of urokinase (uPA), and human lung microvascular endothelial cells (HLMVEC), expressing high amounts of this enzyme. We have used wild-type PAI-1 (wPAI-1) (t(1/2) = 1.6 h) and PAI-1 cysteine mutants (CysPAI-1) characterized by their prolonged half-life time (hDbetaT) (t(1/2) = 63.6 h and t(1/2) = 7,000 h). We have observed a significant inhibitory dose-dependent effect exerted by the CysPAI-1s on sprout formation by HUVEC and HLMVEC cells. The inhibition rate was considerably stronger in lung capillary cell cultures and significantly more pronounced for CysPAI-1 mutants with longer anti-uPA activity (betaT). wPAI-1 with a short anti-proteolytic half-life has induced sprout formation in HUVEC, but not in HLMVEC cultures. This difference in behavior was most likely related to the presence of excessive amounts of uPA in HLMVEC cells and the known mechanism of clearing PAI-1/uPA/uPAR complexes from the cell surface. A less efficient system of HUVEC cells might give wPAI-1 the chance to interact with non-proteolytic pathways of angiogenesis stimulation. We conclude that while the anti-proteolytic properties of PAI-1 constructs are preserved, these proteins inhibit angiogenesis and inhibitory activity dominates over any stimulatory effects of PAI-1.
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PMID:Plasminogen activator inhibitor type-1 mutants regulate angiogenesis of human umbilical and lung vascular endothelial cells. 1554 31


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