THE INFLUENCE OF GLUCOCORTICOID HORMONES ON THE GENE TRANSCRIPTION OF POUR COMPONENTS OF THE FIBRINOLYTIC SYSTEM

1987 ◽  
Author(s):  
R L Medcalf ◽  
E van den Berg ◽  
W-D Schleuning
Keyword(s):  
Gene Transcription ◽  
Hormonal Regulation ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Glucocorticoid Hormones ◽  
Regulation Of Biosynthesis ◽  
Matrix Stability ◽  
Cloned Cdna ◽  
Pai 1

The hormonal regulation of plasminogen activator (urokinase type (u-PA) and tissue-type (t-PA)) biosynthesis plays an important role in fibrinolysis and extracellular matrix turnover during invasive growth and cell migration. Recently, two genetically distinct inhibitors of both PA's (PA inhibitor 1 (PAI-1) and PA inhibitor 2 (PAI-2)) have been described which may contribute to the modulation of matrix stability. We have employed cloned cDNA probes to study the regulation of biosynthesis of these proteins in the human fibrosarcoma line HT1080. These cells constitutively express high levels of pro-u-PA. PAI-1, PAI-2 and t-PA are also present at relatively low levels. Treatment of the cells with the glucocorticoid dexamethasone (Dex; 10−7 M), almost completely suppresses u-PA gene transcription, as determined by measurement of in vitro elongation of initiated u-PA transcripts in isolated nuclei ("run-on" transcription assay). Concomitantly, Dex also induces PAI-1 and t-PA gene transcription, whereas PAI-2 gene transcription appeared to remain ' unaffected. These changes in transcription rates are also reflected at the level of mRNA: u-PA mRNA is decreased, whereas PAI-1 and t-PA mRNA are simultaneously induced. PAI-2 mRNA is apparently unchanged. These results demonstrate that glucocorticoid hormones reprogramne the expression of components of the fibrinolytic system, and are of possible relevance in the context of inflammatory disease and malignancy.

Differential Role of Components of the Fibrinolytic System in the Formation and Removal of Thrombus Induced by Endothelial Injury

1999 ◽  
Vol 81 (04) ◽  
pp. 601-604 ◽  
Author(s):  
Hiroyuki Matsuno ◽  
Osamu Kozawa ◽  
Masayuki Niwa ◽  
Shigeru Ueshima ◽  
Osamu Matsuo ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Thrombus Formation ◽  
Endothelial Injury ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Wild Type ◽  
Type Plasminogen Activator ◽  
Pai 1

SummaryThe role of fibrinolytic system components in thrombus formation and removal in vivo was investigated in groups of six mice deficient in urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA), or plasminogen activator inhibitor-1 (PAI-1) (u-PA-/-, t-PA-/- or PAI-1-/-, respectively) or of their wild type controls (u-PA+/+, t-PA+/+ or PAI-1+/+). Thrombus was induced in the murine carotid artery by endothelial injury using the photochemical reaction between rose bengal and green light (540 nm). Blood flow was continuously monitored for 90 min on day 0 and for 20 min on days 1, 2 and 3. The times to occlusion after the initiation of endothelial injury in u-PA+/+, t-PA+/+ or PAI-1+/+ mice were 9.4 ± 1.3, 9.8 ± 1.1 or 9.7 ± 1.6 min, respectively. u-PA-/- and t-PA-/- mice were indistinguishable from controls, whereas that of PAI-1-/- mice were significantly prolonged (18.4 ± 3.7 min). Occlusion persisted for the initial 90 min observation period in 10 of 18 wild type mice and was followed by cyclic reflow and reocclusion in the remaining 8 mice. At day 1, persistent occlusion was observed in 1 wild type mouse, 8 mice had cyclic reflow and reocclusion and 9 mice had persistent reflow. At day 2, all injured arteries had persistent reflow. Persistent occlusion for 90 min on day 0 was observed in 3 u-PA-/-, in all t-PA-/- mice at day 1 and in 2 of the t-PA-/-mice at day 2 (p <0.01 versus wild type mice). Persistent patency was observed in all PAI-1-/- mice at day 1 and in 5 of the 6 u-PA-/- mice at day 2 (both p <0.05 versus wild type mice). In conclusion, t-PA increases the rate of clot lysis after endothelial injury, PAI-1 reduces the time to occlusion and delays clot lysis, whereas u-PA has little effect on thrombus formation and spontaneous lysis.

Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 328-333 ◽  
Author(s):  
N J de Fouw ◽  
Y F de Jong ◽  
F Haverkate ◽  
R M Bertina
Keyword(s):  
Plasminogen Activator ◽  
Protein C ◽  
Blood Platelets ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Tissue Type ◽  
Clot Lysis ◽  
Activator Inhibitor ◽  
Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

Influence of insulin-induced hypoglycemia on the hemostatic and fibrinolytic system in patients with hypothalamicpituitary disorders

1998 ◽  
Vol 18 (02) ◽  
pp. 74-79
Author(s):  
K.-H. Zurborn ◽  
H. D. Bruhn ◽  
H. Mönig
Keyword(s):  
Factor Viii ◽  
Plasminogen Activator ◽  
Tolerance Test ◽  
Insulin Tolerance Test ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Insulin Tolerance ◽  
Factor Viii Antigen ◽  
Pai 1 ◽  
D Dimer

SummaryIn order to study the acute and prolonged effects of hypoglycemia on the hemostatic and fibrinolytic system we measured prothrombin fragment (F1+2), thrombin-antithrombin III complex (TAT), platelet factor 4 (PF4), β-thromboglobulin (âTG), factor VIII antigen (F VIII antigen), D-dimer, tissue-type plasminogen activator (t-PA) antigen, and plasminogen activator inhibitor (PAI-1) in 22 patients during insulin tolerance test. F1+2 and TAT increased significantly 15 and 90 minutes after administration of insulin, as did PF4 and âTG. At 4 and 24 hours, these parameters were not different from baseline. Factor VIII antigen was not significantly altered. D-dimer concentration did not change. However, the D-dimer/TAT ratio significantly decreased at 15 and 90 minutes but increased markedly above baseline at 4 and 24 hours. t-PA antigen was also found to be elevated at 15 and 90 minutes but had returned to baseline at 4 and 24 hours. PAI-1 concentration did not change. We conclude from these data that both coagulation and fibrinolysis are activated in the short-term response to acute insulin-induced hypoglycemia, followed by a prolonged activation of fibrinolysis. Our study may explain why patients undergoing insulin tolerance test, despite marked clotting and platelet activation, almost never develop thromboembolic complications.

Absence of Synergism Between Tissue-Type Plasminogen Activator (t-PA), Single-Chain UrokinaseType Plasminogen Activator (scu-PA) and Urokinase on Clot Lysis in a Plasma Milieu In Vitro

1986 ◽  
Vol 56 (01) ◽  
pp. 035-039 ◽  
Author(s):  
D Collen ◽  
F De Cock ◽  
E Demarsin ◽  
H R Lijnen ◽  
D C Stump
Keyword(s):  
Human Plasma ◽  
Plasminogen Activator ◽  
Dose Response ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Clot Lysis ◽  
Single Chain ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryA potential synergic effect of tissue-type plasminogen activator (t-PA), single-chain urokinase-type plasminogen activator (scuPA) or urokinase on clot lysis was investigated in a whole human plasma system in vitro. The system consisted of a human plasma clot labeled with 125I-fibrinogen, immersed in titrated whole human plasma, to which the thrombolytic agents were added. Clot lysis was quantitated by measurement of released 125I, and activation of the fibrinolytic system in the surrounding plasma by measurements of fibrinogen and α2-antiplasmin.t-PA, scu-PA and urokinase induced a dose-dependent and time-dependent clot lysis; 50 percent lysis after 2 h was obtained with 5 nM t-PA, 20 nM scu-PA and 12 nM urokinase. At these concentrations no significant activation of the fibrinolytic system in the plasma was observed with t-PA and scu-PA, whereas urokinase caused significant α2-antiplasmin consumption and concomitant fibrinogen degradation. The shape of the dose-response curves was different; t-PA and urokinase showed a log linear dose-response whereas that of scu-PA was sigmoidal.

Abstract T P75: Temporal Profiles of Plasminogen Activator Inhibitor-1 Concentration and Activity Changes in Circulation after Focal Stroke and Tissue Type Plasminogen Activator Administration in Rats

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Qi Liu ◽  
Xiang Fan ◽  
Helen Brogren ◽  
Ming-Ming Ning ◽  
Eng H Lo ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Temporal Profiles ◽  
Activator Inhibitor ◽  
Pai 1

Aims: Plasminogen activator inhibitor-1 (PAI-1) is the main and potent endogenous tissue-type plasminogen activator (tPA) inhibitor, but an important question on whether PAI-1 in blood stream responds and interferes with the exogenously administered tPA remains unexplored. We for the first time investigated temporal profiles of PAI-1 concentration and activity in circulation after stroke and tPA administration in rats. Methods: Permanent MCAO focal stroke of rats were treated with saline or 10mg/kg tPA at 3 hours after stroke (n=10 per group). Plasma (platelet free) PAI-1 antigen and activity levels were measured by ELISA at before stroke, 3, 4.5 (1.5 hours after saline or tPA treatments) and 24 hours after stroke. Since vascular endothelial cells and platelets are two major cellular sources for PAI-1 in circulation, we measured releases of PAI-1 from cultured endothelial cells and isolated platelets after direct tPA (4 μg/ml) exposures for 60 min in vitro by ELISA (n=4 per group). Results: At 3 hours after stroke, both plasma PAI-1 antigen and activity were significantly increased (3.09±0.67, and 3.42±0.57 fold of before stroke baseline, respectively, all data are expressed as mean±SE). At 4.5 hours after stroke, intravenous tPA administration significantly further elevated PAI-1 antigen levels (5.26±1.24), while as expected that tPA neutralized most elevated PAI-1 activity (0.33±0.05). At 24 hours after stroke, PAI-1 antigen levels returned to the before baseline level, however, there was a significantly higher PAI-1 activity (2.51±0.53) in tPA treated rats. In vitro tPA exposures significantly increased PAI-1 releases into culture medium in cultured endothelial cells (1.65±0.08) and platelets (2.02±0.17). Conclution: Our experimental results suggest that tPA administration may further elevate stroke-increased blood PAI-1 concentration, but also increase PAI-1 activity at late 24 hours after stroke. The increased PAI-1 releases after tPA exposures in vitro suggest tPA may directly stimulate PAI-1 secretions from vascular walls and circulation platelets, which partially contributes to the PAI-1 elevation observed in focal stroke rats. The underlying regulation mechanisms and pathological consequence need further investigation.

scholarly journals HSP47 regulates ECM accumulation in renal proximal tubular cells induced by TGF-β1 through ERK1/2 and JNK MAPK pathways

2012 ◽  
Vol 303 (5) ◽  
pp. F757-F765 ◽  
Author(s):  
Hong-bo Xiao ◽  
Rui-hong Liu ◽  
Guang-hui Ling ◽  
Li Xiao ◽  
Yuan-chen Xia ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Transforming Growth Factor ◽  
Underlying Mechanism ◽  
Tissue Type ◽  
Ecm Proteins ◽  
Signaling Events ◽  
Proximal Tubular ◽  
Pai 1

Heat shock protein (HSP)47 is a collagen-specific molecular chaperone that is essential for the biosynthesis of collagen molecules. It is likely that increased levels of HSP47 contribute to the assembly of procollagen and thereby cause an excessive accumulation of collagens in disease processes associated with fibrosis. Although HSP47 promotes renal fibrosis, the underlying mechanism and associated signaling events have not been clearly delineated. We examined the role of HSP47 in renal fibrosis using a rat unilateral ureteral obstruction model and transforming growth factor (TGF)-β1-treated human proximal tubular epithelial (HK-2) cells. An upregulation of HSP47 in both in vivo and in vitro models was observed, which correlated with the increased synthesis of extracellular matrix (ECM) proteins and expression of tissue-type plasminogen activator inhibitor (PAI)-1. Blockade of HSP47 by short interfering RNA suppressed the expression of ECM proteins and PAI-1. In addition, TGF-β1-induced HSP47 expression in HK-2 cells was attenuated by ERK1/2 and JNK MAPK inhibitors. These data suggest that ERK1/2 and JNK signaling events are involved in modulating the expression of HSP47, the chaperoning effect of which on TGF-β1 would ultimately contribute to renal fibrosis by enhancing the synthesis and deposition of ECM proteins.

Progress of fibrinolysis during tumor necrosis factor infusions in humans. Concomitant increase in tissue-type plasminogen activator, plasminogen activator inhibitor type-1, and fibrin(ogen) degradation products

Blood ◽  
1990 ◽  
Vol 76 (11) ◽  
pp. 2284-2289 ◽  
Author(s):  
VW van Hinsbergh ◽  
KA Bauer ◽  
T Kooistra ◽  
C Kluft ◽  
G Dooijewaard ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Tumor Necrosis Factor ◽  
Plasminogen Activator ◽  
Tumor Necrosis ◽  
Degradation Products ◽  
Tissue Type ◽  
Necrosis Factor ◽  
Pai 1

Abstract Several investigators have reported that tumor necrosis factor (TNF) can alter the production of plasminogen activator type-1 (PAI-1) and plasminogen activators (PAs) by endothelial cells in vitro. We have examined the in vivo effects of recombinant human TNF administration on fibrinolysis as assessed by parameters in plasma during a 24-hour period of continuous TNF infusion to 17 cancer patients with active disease. The plasma levels of PAI activity increased sevenfold after 3 and 24 hours of TNF infusion. This was the result of an increase of PAI- 1 antigen; PAI-2 antigen was not detectable. Plasma concentrations of tissue-type PA (t-PA) antigen increased twofold to fivefold after 3 and 24 hours of TNF infusion, whereas urokinase-type PA antigen levels in plasma remained unaltered. After 3 hours of TNF infusion the plasma levels of alpha 2-antiplasmin were slightly decreased, 5% on average, suggesting that fibrinolysis continued. After 24 hours of TNF infusion a highly significant increase in fibrin- plus fibrinogen-degradation products, and separately of fibrin degradation products and fibrinogen degradation products, was found. This indicates that fibrinolysis persisted, at least partly, in the presence of high levels of PAI activity. Whereas PAI-1 production increased, t-PA production by human endothelial cells in vitro remains unaltered or even decreases on TNF addition. It has been shown previously that TNF infusion in our patients results in thrombin and fibrin generation. Therefore, it is possible that thrombin, not TNF, is the actual stimulus for t-PA production in our patients. We speculate that fibrin is formed during TNF infusions and that plasmin is generated by t-PA action immediately on the initial formation of (soluble) fibrin molecules. Such a process may explain the generation of degradation products of both fibrin and fibrinogen during infusion of TNF in patients.

scholarly journals Inhibition of clot lysis and decreased binding of tissue-type plasminogen activator as a consequence of clot retraction

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1420-1427 ◽  
Author(s):  
S Kunitada ◽  
GA FitzGerald ◽  
DJ Fitzgerald
Keyword(s):  
Plasminogen Activator ◽  
Tissue Type ◽  
Clot Lysis ◽  
Plasminogen Activator Inhibitor 1 ◽  
Clot Retraction ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Pai 1

Tissue-type plasminogen activator (t-PA) is less active in vivo and in vitro against clots that are enriched in platelets, even at therapeutic concentrations. The release of radioactivity from 125I-fibrin-labeled clots was decreased by 47% 6 hours after the addition of t-PA 400 U/mL when formed in platelet-rich versus platelet-poor plasma. This difference was not due to the release of plasminogen activator inhibitor-1 (PAI-1) by platelets. Thus, the fibrinolytic activity of t- PA in the supernatant was similar in the two preparations and fibrin autography demonstrated only a minor degree of t-PA-PAI-1 complex formation. Furthermore, a similar platelet-dependent reduction in clot lysis was seen with a t-PA mutant resistant to inhibition by PAI-1. The reduction in t-PA activity correlated with a decrease in t-PA binding to platelet-enriched clot (60% +/- 3% v platelet-poor clot, n = 5). This reduction in binding was also shown using t-PA treated with the chloromethylketone, D-Phe-Pro-Arg-CH2Cl (PPACK) (36% +/- 13%, n = 3), and with S478A, a mutant t-PA in which the active site serine at position 478 has been substituted by alanine (43% +/- 6%, n = 3). In contrast, fixed platelets and platelet supernatants had no effect on the binding or lytic activity of t-PA. Pretreatment with cytochalasin D 1 mumol/L, which inhibits clot retraction, also abolished the platelet- induced inhibition of lysis and t-PA binding by platelets. These data suggest that platelets inhibit clot lysis at therapeutic concentrations of t-PA as a consequence of clot retraction and decreased access of fibrinolytic proteins.

Anti-apoptotic roles of plasminogen activator inhibitor-1 as a neurotrophic factor in the central nervous system

2008 ◽  
Vol 100 (12) ◽  
pp. 1014-1020 ◽  
Author(s):  
Satoru Koyanagi ◽  
Yukako Kuramoto ◽  
Masahiko Kimura ◽  
Masatoshi Oda ◽  
Tomohiro Kozako ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Plasminogen Activator Inhibitor 1 ◽  
The Central Nervous System ◽  
Activator Inhibitor ◽  
Pai 1

SummaryPlasminogen activator inhibitor-1 (PAI-1), a member of the ser-pin gene family, is the primary inhibitor of urokinase-type and tissue-type PA s.PA I-1 plays an important role in the process of peripheral tissue remodeling and fibrinolysis through the regulation of PA activity. This serpin is also produced in brain tissues and may regulate the neural protease sequence in the central nervous system (CNS), as it does in peripheral tissues. In fact, PA I-1 mRNA is up-regulated in mouse brain after stroke.The serpin activity of PA I-1 helps to prevent tissue-type PA -induced neuron death.However, we have previously found that PAI-1 has a novel biological function in the CNS: the contribution to survival of neurites on neurons. In neuronally differentiated rat pheochromocytoma (PC-12) cells, a deficiency of PA I-1 in vitro caused a significant reduction in Bcl-2 and Bcl-XL mRNAs and an increase in Bcl-XS and Bax mRNAs.The change in the balance between mRNA expressions of the anti- and pro-apoptotic Bcl-2 family proteins promoted the apoptotic sequence: cas-pase-3 activation, cytochrome c release from mitochondria and DNA fragmentation. Our results indicate that PA I-1 has an antiapoptotic role in neurons.PAI-1 prevented the disintegration of the formed neuronal networks by maintaining or promoting neuroprotective signaling through the MAPK/ ERK pathway, suggesting that the neuroprotective effect of PAI-1 is independent of its action as a protease inhibitor. This review discusses the neuroprotective effects of PA I-1 in vitro, together with the relevant data from other laboratories. Special emphasis is placed on its action on PC-12 cells.

Association between inflammatory mediators and the fibrinolysis system in infectious pleural effusions

2003 ◽  
Vol 105 (5) ◽  
pp. 601-607 ◽  
Author(s):  
Carmen ALEMÁN ◽  
José ALEGRE ◽  
Jasone MONASTERIO ◽  
Rosa M. SEGURA ◽  
Lluís ARMADANS ◽  
...  
Keyword(s):  
Pleural Fluid ◽  
Inflammatory Mediators ◽  
Pearson Correlation ◽  
Fibrinolytic System ◽  
Tissue Type ◽  
Rank Test ◽  
Pleural Effusions ◽  
Polymorphonuclear Elastase ◽  
Tnf Α ◽  
Pai 1

The response of the fibrinolytic system to inflammatory mediators in empyema and complicated parapneumonic pleural effusions is still uncertain. We prospectively analysed 100 patients with pleural effusion: 25 with empyema or complicated parapneumonic effusion, 22 with tuberculous effusion, 28 with malignant effusion and 25 with transudate effusion. Inflammatory mediators, tumour necrosis factor-α (TNF-α), interleukin-8 (IL-8) and polymorphonuclear elastase, were measured in serum and pleural fluid. Fibrinolytic system parameters, plasminogen, tissue-type plasminogen activator (t-PA) and urokinase PA, PA inhibitor type 1 (PAI 1) and PAI type 2 concentrations and PAI 1 activity, were quantified in plasma and pleural fluid. The Wilcoxon signed-rank test was used to compare plasma and pleural values and to compare pleural values according to the aetiology of the effusion. The Pearson correlation coefficient was used to assess the relationship between fibrinolytic and inflammatory markers in pleural fluid. Significant differences were found between pleural and plasma fibrinolytic system levels. Pleural fluid exudates had higher fibrinolytic levels than transudates. Among exudates, tuberculous, empyema and complicated parapneumonic effusions demonstrated higher pleural PAI levels than malignant effusions, whereas t-PA was lowest in empyema and complicated parapneumonic pleural effusions. PAI concentrations correlated with TNF-α, IL-8 and polymorphonuclear elastase when all exudative effusions were analysed, but the association was not maintained in empyema and complicated parapneumonic effusions. A negative association found between t-PA and both IL-8 and polymorphonuclear elastase in exudative effusions was strongest in empyema and complicated parapneumonic effusions. Blockage of fibrin clearance in empyema and complicated parapneumonic effusions was associated with both enhanced levels of PAIs and decreased levels of t-PA.

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