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PubMed1991

Localization of blood coagulation factors and fibrinolysis factors within lymphoid germinal centers in human lymph nodes.

The presence of nineteen blood coagulation factors and fibrinolysis factors was immunohistochemically evaluated in human lymph node germinal centers (GCs). Twelve of these factors were detected within lymphoid GCs. The predominant pattern was dendritic with occasional crescent-shaped, ring-shaped or 'moth-eaten' appearance. Immunostains of factor VIII-related antigen, factor I, protein C, tetranectin, antithrombin III, type 2-plasminogen activator inhibitor, and alpha 2-plasmin inhibitor were almost entirely absent from GCs, although they reacted in vascular wall and lumen, respectively. The immunostaining to high molecular weight kininogen, kallikrein, factors XII, X, V, II, XIIIa, XIIIs, plasminogen, tissue-plasminogen activator, and type 1-plasminogen activator inhibitor more frequently revealed a positive dendritic pattern. Immuno-electron microscopy demonstrated factor X and factor XIIIa attached to the cell surfaces of lymphocytes, macrophages, and follicular dendritic cells (FDCs); and in the intercellular space within GCs, especially attached to the labyrinthine-like structure of FDCs. No reaction products were observed in the perinuclear cisternae and rough endoplasmic reticulum in either lymphocytes or FDCs. Our data demonstrate that human lymphoid GCs really contain some of the proteins related to the blood coagulation and fibrinolysis cascades.

Dendritic Cells↗
PubMed1989

Increased tissue-plasminogen activator (t-PA) levels in patients under oral anticoagulant therapy.

The fibrinolytic system was investigated in 30 patients under oral anticoagulant therapy, and in 23 control patients not receiving oral anticoagulants. Patients under oral anticoagulant therapy had significantly higher tissue-plasminogen activator (t-PA) antigen levels than patients in the control group. Mean t-PA levels before venous occlusion were 18.4 ng/ml in the anticoagulated patients vs. 7.9 ng/ml in the control patients (p less than 0.001). After venous occlusion for 10 minutes, t-PA levels were 45.0 ng/ml in the anticoagulated patients and 24.2 ng/ml in the control patients (p less than 0.01). Plasminogen activator inhibitor (PAI) capacity was not significantly different in the two groups before venous occlusion (VO) but differed slightly (p less than 0.05) after VO. The net decrease in euglobulin lysis time (ELT) after venous occlusion (= ELT before VO - ELT after VO), indicating the relative potency of the fibrinolytic activity in blood, was also significantly higher in the anticoagulated patients (median 240 min vs. 125 min, p less than 0.001). These data indicate that oral anticoagulant therapy increases the fibrinolytic activity in blood, and thus may have an additional therapeutic effect in addition to anticoagulation.

4-Hydroxycoumarins↗
PubMed1995

Analysis of plasma fibrinolysis in the patients with acute cerebral infarction.

In the present study, the plasma fibrinolytic activity in 30 cases of cortical artery territory cerebral infarction (CACI) and 32 cases of perforating artery territory cerebral infarction (PACI) within 3 days after ictus, and 30 sex- and age-matched controls without cardio-cerebrovascular diseases were evaluated by a comprehensive panel of assay, including the plasma tPA activity, PAI activity, endothelial capacity of tPA release and PAI/tPA ratio. The results showed that the plasma fibrinolysis and the endothelial potential to release tPA responding to stimulation in both subtypes of the patients were significantly lower than those in the controls, which provide the theoretical basis for carrying out the thrombolytic therapy in the ischemic stroke. And the study also suggested that increased plasma PAI activity could increase the risk of AS thrombotic events with increased serum triglyceride level.

Acute Disease↗
PubMed1988

Impaired fibrinolysis in coronary artery disease.

We assessed endogenous endothelial-dependent fibrinolysis in 99 subjects with coronary artery disease (CAD) documented by angiography and in 28 control subjects with normal coronary arteries on angiography. We used specific, sensitive assays for plasma tissue-type plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor (PAI) activity, plasminogen, and alpha-2 plasmin inhibitor (alpha-2 PI). Mean PAI activity was significantly higher, and mean t-PA activity after venous occlusion of the upper arm (a standard test of the capacity of vascular endothelium to release t-PA) was significantly lower in subjects with CAD than in subjects with normal coronary arteries. The mean increment in t-PA antigen after venous occlusion was significantly lower than normal in subjects with CAD with onset of symptoms before age 45 years. Subjects with CAD had a significantly increased mean plasma fibrinogen level compared with control subjects, and a significant positive correlation was observed between PAI activity and plasma fibrinogen in subjects with CAD. No significant abnormalities of plasminogen or alpha-2 PI were observed in any subset of subjects with CAD. These data support an association between impaired fibrinolysis and CAD, with contributions from both increased PAI activity and in younger subjects from reduced endothelial t-PA release.

Antigens↗
PubMed1989

Correlation of baseline plasminogen activator inhibitor activity with patency of the infarct artery after thrombolytic therapy in acute myocardial infarction.

Increased levels of plasminogen activator inhibitor (PAI) have recently been described in patients with acute myocardial infarction (AMI). To correlate PAI levels to patency of infarct arteries after thrombolytic therapy with recombinant tissue-type plasminogen activator (rt-PA), 125 consecutive patients with AMI were examined. Blood levels of fibrinogen, plasminogen, tissue plasminogen activator (t-PA) and PAI were measured before treatment initiation, 10 minutes after completion of rt-PA infusion and 24 and 48 hours after treatment. Coronary angiography, performed in all patients 72 hours after beginning rt-PA infusion, revealed patent infarct arteries in 97 patients and occluded infarct arteries in 28 patients. Pretreatment levels of PAI were significantly higher in patients with occluded infarct arteries (18.0 +/- 11.5 vs 10.5 +/- 9.3 IU/ml, p less than 0.01). Conceivably, higher levels of PAI may interfere with the natural thrombolytic process and make pharmacologic thrombolytic intervention less effective.

Arteries↗
PubMed1991

Increased fibrinolytic potential induced by gliclazide in types I and II diabetic patients.

This study examined the effect of gliclazide on tissue-type plasminogen activator (t-PA)-related fibrinolysis in 23 Type I diabetic patients without residual beta-cell function and 17 Type II diabetic patients initially treated with tolbutamide. The Type I diabetic patients received gliclazide for a period of 6 months; the Type II diabetic patients were shifted from tolbutamide to gliclazide. In Type I diabetic patients, after 2-3 months of treatment with gliclazide, we observed a significant increase in plasma concentrations of total t-PA antigen that remained stable until discontinuation of the drug (p less than 0.0002), whereas the plasma concentrations of plasminogen activator inhibitor (PAI) did not change significantly during the study. Next, we investigated the possibility of gliclazide inducing t-PA-related fibrinolysis in a subset of Type II diabetics without detectable concentrations of t-PA during treatment with tolbutamide. The concentrations of active t-PA increased significantly 3 months after a change in treatment to gliclazide, and active t-PA again decreased in one patient to undetectable levels after 12 months with gliclazide. Moreover, the plasma concentrations of total t-PA antigen increased significantly (p less than 0.02) in this group of diabetic patients while PAI remained unchanged. The changes in t-PA-related fibrinolysis could not be related in either Type I or Type II diabetics to changes in metabolic state evaluated by blood glucose, HbA1c, cholesterol, triglycerides, or apolipoproteins A and B. We conclude that gliclazide has the potential to exert extrametabolic non-insulin-mediated effects on t-PA-related fibrinolysis in diabetic patients.

Adult↗
PubMed1990

Tissue-plasminogen activator stimulates endothelial cell migration in wound assays.

The ability of tissue plasminogen activator (tPA) to induce human umbilical vein endothelial (HUVE) cell migration was studied using an in vitro, serum-free wound assay system. At pharmacological doses, tPA stimulated HUVE cell migration dose-dependently. Treatment of cells with epsilon amino caproic acid (EACA) to detach cell-surface and extracellular matrix bound plasminogen, which could lead to plasmin generation, resulted in increased HUVEcell migration on stimulation with tPA.Plasminogen activator inhibitor-1 (PAI-1), a natural plasminogen activator inhibitor, abolished tPA-induced HUVEcell migration. These results demonstrate for the first time that tPA is capable of stimulating endothelial cell migration in wound assays and this effect is susceptible to PAI-1 inhibition.

Cell Movement↗
PubMed1991

The plasminogen activator inhibitor-1 binding site in the kringle-2 domain of tissue-type plasminogen activator.

We have shown that synthetic peptides containing the amino acid sequence Asn-Arg-Arg-Leu, derived from the amino acid sequence of the inner loop of the kringle-2 domain of tissue-type plasminogen activator (tPA), inhibited complex formation between two chain tPA and plasminogen activator inhibitor-1 (PAI-1) by binding to PAI-1. This binding was reversible and was inhibited by not only tPA but also by enzymatically inactive tPA. Quantitative analyses of the interaction of PAI-1 with the peptide containing the Asn-Arg-Arg-Leu sequence indicated that the PAI-1 binding site residues in the inner loop of the kringle-2 domain and is preferentially expressed in two chain tPA.

Amino Acid Sequence↗
PubMed1991

Extracellular and cell-associated localizations of plasminogen activators and plasminogen activator inhibitor-1 in cultured endothelium.

The extracellular localizations of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were examined in cultured bovine capillary endothelial cells (BCEs) by an immunofluorescence method using BCEs treated with or without saponin and focal contact preparations. The specific immunofluorescence of cell surface uPA showed a patchy or strand-like distribution and was colocalized with vinculin strands indicating that uPA secreted from BCEs was mainly deposited at the cell surface of focal contacts. BCEs at a subconfluent density showed a higher intensity of specific immunofluorescence for uPA than when they were at a confluent density. tPA was observed over the dorsal surface of cultured BCEs and accentuated at their margins, suggesting that tPA was diffusely distributed on the luminal surface of BCEs in vivo. PAI-1 was distributed in the extracellular matrix under cultured BCEs. These findings suggest that uPA and PAI-1 are located under BCEs participating in the regulation of proteolytic activities provoked by plasminogen-PAs-plasmin system in vivo. The localization of tPA appears to be consistent with its function, which is to maintain the fluidity of the blood and to initiate thrombolysis in vivo.

Actins↗
PubMed1991

Tumor necrosis factor and epidermal growth factor modulate migration of human microvascular endothelial cells and production of tissue-type plasminogen activator and its inhibitor.

Epidermal growth factor (EGF) induces tubular formation of cultured human microvascular endothelial (HME) cells in the gel matrix containing collagen, and tumor necrosis factor (TNF) disrupts the tubular formation (Mawatari et al. (1989) J. Immunol. 143, 1619-1627). Here we studied the effects of EGF and TNF on endothelial cell migration and on the production of proteases. Confluent HME cells, when wounded with a razor blade, moved into the denuded space. This migration was stimulated by EGF and inhibited by TNF in this assay and in the Boyden chamber assay. Antibody against tissue-type plasminogen activator (t-PA) inhibited the EGF-stimulated cell migration in both assays by approximately 70%, but antibody against urokinase-type plasminogen activator (u-PA) could not inhibit its migration. Quantitative immunoreactive assays showed an approximately three- to fourfold increase of t-PA at 6 to 12 h after EGF addition, and TNF inhibited the production of t-PA by 50%. Northern blot analysis showed increased expression of t-PA mRNA by EGF alone in a time- and dose-dependent manner, whereas TNF alone inhibited its expression in a time- and dose-dependent manner. Northern blot analysis showed a significant increase of plasminogen activator inhibitor-1 (PAI-1) mRNA when EGF or TNF was present. Stimulation by EGF of cell migration of HME cells and its inhibition by TNF appear to be closely correlated with the cellular modulation of t-PA and PAI-1 activities.

Cell Movement↗
PubMed1992

Disruption of microtubules inhibits the stimulation of tissue plasminogen activator expression and promotes plasminogen activator inhibitor type 1 expression in human endothelial cells.

The expression of certain proteolytic enzymes involved in cell migration (collagenase, urokinase) can be enhanced by the disruption of cellular cytoskeletal organization, suggesting an association between cell shape and gene expression. We have examined the effect of cytoskeleton-disrupting agents on the production and secretion of another proteolytic enzyme, tissue plasminogen activator (tPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), in human endothelial cells. Addition of 1 x 10(-6) M colchicine, 5 x 10(-6) M cytochalasin B, 10(-6) M nocodazole, or 10(-6) M tubulazole had no effect on the constitutive rate of release of tPA. However, the three microtubule-disrupting agents--colchicine, nocodazole, and tubulazole--depressed the stimulation of tPA secretion by phorbol myristate acetate (PMA) by 50- to 65%. Disruption of microfilament structure by cytochalasin B had no effect. In contrast, microtubule disruption in the absence or presence of PMA stimulated PAI-1 secretion by 2.5 and 2 times, respectively. The depression of tPA secretion was not due to inhibition of the secretory function since tPA did not accumulate intracellularly during colchicine treatment. Nor did colchicine affect the PMA activation of protein kinase C-alpha, upon which stimulation of tPA is dependent; neither translocation of the kinase nor phosphorylation of the protein kinase C substrate protein, P80, was inhibited. Measurement of tPA mRNA levels demonstrated that the increase which precedes PMA-enhanced tPA secretion was also inhibited by colchicine by 50%. However, tPA gene transcriptional activity was only reduced 13%, suggesting that a post-transcriptional event was affected by microtubule disruption. PAI-1 mRNA levels and transcription rates were elevated 3.5 times. This study suggests that the changes that occur in endothelial cells during PMA-induced signal transmission leading to enhanced tPA mRNA levels and tPA antigen production can be partly blocked by agents that disrupt microtubule organization.

Cells, Cultured↗
PubMed1986

Plasminogen activators catalyse conversion of inhibitor from fibrosarcoma cells to an inactive form with a lower apparent molecular mass.

Purified approximately 54 kDa plasminogen activator inhibitor from human fibrosarcoma cells was converted to an inactive form with slightly higher electrophoretic mobility by incubation with catalytic amounts of urokinase-type or tissue-type plasminogen activator. Serine proteinase inhibitors and a monoclonal antibody against urokinase-type plasminogen activator inhibited the conversion, indicating that it was caused by plasminogen activator-catalyzed proteolysis. These findings represent the first demonstration of a well-defined protein apart from plasminogen, constituting a substrate for plasminogen activators.

Cell Line↗
PubMed1991

Imbalance of plasminogen activators and their inhibitors in human colorectal neoplasia. Implications of urokinase in colorectal carcinogenesis.

Neoplastic growth and metastatic spread of adenocarcinomas is characterized by a marked increase of urokinase-type plasminogen activator (u-PA) and a decrease of tissue-type plasminogen activator (t-PA). In this study, the authors determined the activity and antigen levels of u-PA and t-PA, and their inhibitors, plasminogen-activator inhibitors types 1 and 2 (PAI-1 and PAI-2), in normal mucosa, adenomatous polyps, and adenocarcinomas of the human colon. The decrease in t-PA activity in the neoplastic tissues, determined enzymatically and zymographically, was significantly correlated with an increase in PAI-1 and PAI-2, in particular in carcinomas. In spite of significantly higher inhibitor levels in the neoplastic tissues, u-PA was found to be increased as well, both in antigen level and in activity. The authors conclude that PAI-1 and PAI-2 are significantly increased in neoplastic tissue of the human colon and contribute considerably to the decrease of t-PA activity in carcinomas. However, the malignancy-associated increase in u-PA seems not to be affected by the plasminogen activator inhibitors. Thus, it appears that there is an imbalance between plasminogen activators and their inhibitors in colonic neoplasia in favor of u-PA, which may contribute to plasmin-mediated growth, invasiveness, and metastasis. This feature was also noticed in adenomatous polyps, supporting the malignant potency of adenomas.

Adenocarcinoma↗
PubMed1988

Inhibition of plasminogen activators and the growth of cultured human tumour cells.

1. Inhibition of a human fibroblast cell-surface proteinase with alpha-1-antitrypsin also inhibited cell proliferation, confirming earlier observations. 2. Although a similar proteinase inhibition could be observed with human tumour cells, the growth of these cells was unaffected. 3. Plasminogen activators on the cell surface and in culture media could be inhibited with specific antibodies, but there was no corresponding effect on the growth of any of the cell types tested.

Antibodies, Monoclonal↗
PubMed1990

Dietary regulation of fibrinolytic factors.

W examined the short-term effects of a high-complex carbohydrate, low fat diet on the plasmin-dependent fibrinolytic pathway. A population of 27 adult American Caucasians exposed to the diet for 3 weeks showed highly significant reductions in the levels of plasminogen (P = 0.0001), tissue plasminogen activator (tPA) (P = 0.0001) and plasminogen activator inhibitor (tPAI) (P = 0.0017). Fibrinogen levels also decreased, but the changes did not reach statistical significance (P = 0.07). In contrast, the levels of the Lpa(a) lipoprotein, a potential inhibitor of fibrinolysis, remained remarkably constant despite a marked decrease in the levels of apolipoprotein B, a major constituent of Lp(a). Correlations between the levels of tPA, tPAI and plasma triglyceride were observed among the individuals both before and after the dietary challenge. Although the mechanisms responsible for the effects are unknown, the dramatic responsiveness of the thrombolytic pathway to dietary challenge is likely to be of importance in understanding the etiology of coronary artery disease and other vascular disorders.

Apolipoproteins↗
PubMed1993

Dietary effects on circadian fluctuation in human blood coagulation factor VII and fibrinolysis.

Six healthy male volunteers were served 4 strictly controlled isoenergetic diets differing in fat (20% or 50% of energy) and fiber contents (2 or 4 g/MJ) for periods of 2 days. The diets were served in random order with at least 5 days separating each diet period. Blood samples for determination of factor VII clotting activity using human (FVIIc) and bovine thromboplastin (FVIIbt), and for assessment of factor VII antigen (FVIIag), tissue-plasminogen activator (t-PA) antigen, plasminogen activator inhibitor-1 (PAI-1) antigen, PAI activity, t-PA and euglobulin fibrinolytic activity, and triglyceride and insulin levels were collected regularly on the second day of each diet period. The high-fat diets resulted in significantly increased postprandial FVIIbt levels (peak values: 131% vs. 95%, P < 0.01), and higher postprandial FVIIbt/FVIIag ratios (peak values: 1.42 vs. 1.16, P < 0.01) compared with the low-fat diets. Fibrinolytic variables were not affected by the dietary changes and consistently showed characteristic U-shaped (t-PA and PAI-1 antigen, PAI activity), or inverted U-shaped (t-PA and euglobulin fibrinolytic activity) circadian patterns with troughs and peaks, respectively, at 17:30-21:30 h. The dietary fiber content had no significant influence on any of the measured variables. Our findings indicate that high-fat diets may increase blood thrombogenicity by virtue of augmented postprandial activation of factor VII.

Adult↗