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PubMed1998

The interaction of Streptococcus dysgalactiae with plasmin and plasminogen.

The activation of plasminogen and the binding of plasmin by bacteria may have many effects which promote infection. The occurrence of such activities in streptococci is well documented; however, these are yet to be demonstrated for S. dysgalactiae. Consequently, the ability of this bacterium to activate mammalian plasminogen and bind either plasmin or its zymogen was investigated. Activation of bovine plasminogen was dependent on both the strain and the growth medium used for cultivation. Eighteen strain were able to activate bovine and ovine plasminogen and some of these also activated plasminogen from the horse, rabbit and pig. None activated human plasminogen and one strain (CE127) did not activate plasminogen from any source. Tricine-SDS PAGE and zymographic analysis of culture supernatants showed that bovine plasminogen was activated by four out of six strains at two locations corresponding to 16 kDa and 10 kDa. Following the growth of five strains in the presence of bovine plasminogen, all but strain CE127 bound high levels of plasmin activity. In contrast, following growth in human plasminogen none of the strains exhibited bound plasmin activity although all could bind human plasmin directly. All strains were also able to bind bovine and human plasminogen in such a way as to allow its activation by urokinase. We conclude that S. dysgalactiae is capable of activating mammalian plasminogen in a species-specific fashion and that the bacterium is also capable of binding plasmin and plasminogen with an apparent preference for bovine plasmin over human plasmin and/or plasminogen from either species.

Animals↗
PubMed2002

Plasminogen activator inhibitor-1 induction after experimental intracerebral hemorrhage.

Serine proteases, such as thrombin and tissue-type plasminogen activator, play an important role in brain injury after intracerebral hemorrhage and other neurologic disorders. Plasminogen activator inhibitor-1 is one of the serine protease inhibitors, or serpins. The balance between serine proteases and serpins may affect the outcome of intracerebral hemorrhage. The purpose of this study was to determine whether plasminogen activator inhibitor-1 and tissue-type plasminogen activator are upregulated after intracerebral hemorrhage and the role that thrombin plays in that induction. Plasminogen activator inhibitor-1 protein levels were upregulated after intracerebral hemorrhage. Brain plasminogen activator inhibitor-1 content also increased after thrombin infusion in a dose-dependent manner. Hirudin, a specific thrombin inhibitor, blocked the upregulation of plasminogen activator inhibitor-1 after intracerebral hemorrhage. Time courses showed that plasminogen activator inhibitor-1 levels around the hematoma peaked at the first day. Plasminogen activator inhibitor-1-positive cells were detected in the perihematomal area and the ipsilateral basal ganglia after thrombin infusion, but not in the contralateral hemisphere. Plasminogen activator inhibitor-1 messenger RNA levels were increased at 24 hours after intracerebral hemorrhage and after thrombin infusion. However, tissue-type plasminogen activator protein levels were the same in the control, whole-blood, and thrombin-infusion groups. In conclusion, intracerebral hemorrhage and thrombin infusion stimulate plasminogen activator inhibitor-1 but not tissue-type plasminogen activator production in the brain. The upregulation of plasminogen activator inhibitor-1 may be neuroprotective by limiting thrombin or other serine protease-induced toxicity.

Animals↗
PubMed1994

Abnormal expression of plasminogen activators in aortic aneurysmal and occlusive disease.

PURPOSE AND METHODS: Aortic aneurysms are characterized by the destruction of the extracellular matrix of the media, whereas occlusive disease involves excess matrix accumulation within the intima. Plasmin degrades extracellular matrix directly and indirectly by activation of latent metalloenzymes. To determine the expression of tissue- and urokinase-type plasminogen activators, immunoassay, fibrin autography, Northern analysis, and immunohistochemistry were performed on specimens of aneurysmal (n = 12), occlusive (n = 8), and healthy (n = 6) aorta. RESULTS: Immunoassay of tissue-type plasminogen activator revealed 8.7 +/- 0.9 ng tissue-type plasminogen activator/mg extracted protein in aneurysmal aorta, 5.7 +/- 0.3 ng/mg in normal aorta, and 2.5 +/- 0.3 ng/mg in occlusive aorta (p < 0.05 for comparisons between all groups). No urokinase-type plasminogen activator antigen was detected by urokinase-type plasminogen activator immunoassay. Fibrin autography exhibited lytic activity at 64 kDa and 54 kDa attributable to tissue-type plasminogen activator and urokinase-type plasminogen activator. The vast majority of fibrinolysis was secondary to free tissue-type plasminogen activator and was greatest in aneurysmal disease and least in occlusive disease. There was only a small amount of lysis secondary to urokinase-type plasminogen activator. Expression of tissue-type plasminogen activator and urokinase-type plasminogen activators mRNA was comparable in aneurysmal and occlusive aortas. In contrast to occlusive disease, aneurysms had an inflammatory cell infiltrate characterized by the expression of urokinase-type plasminogen activator by specific mononuclear cells. Tissue-type plasminogen activator expression was evident in the intima of normal and diseased aorta and in the media of diseased aorta. CONCLUSION: Differential expression of plasminogen activators within the arterial wall may contribute to the unique pathogenesis of aneurysmal and occlusive aortic disease.

Adult↗
PubMed2004

Definition of the structural elements in plasminogen required for high-affinity binding to apolipoprotein(a): a study utilizing surface plasmon resonance.

Lipoprotein(a) [Lp(a)] is suggested to link atherosclerosis and thrombosis owing to the similarity between the apolipoprotein(a) [apo(a)] moiety of Lp(a) and plasminogen. Lp(a) may interfere with tPA-mediated plasminogen activation in fibrinolysis, thereby generating a hypercoaguable state in vivo. The present study employed surface plasmon resonance (SPR) to examine the binding interaction between plasminogen and a physiologically relevant, 17-kringle recombinant apo(a) species [17K r-apo(a)] in real time. Native, intact Glu(1)-plasminogen bound to apo(a) with substantially higher affinity (K(D) approximately 0.3 microM) compared to a series of plasminogen fragments (K1-5, K1-3, K4, K5P, and tail domain) that interacted weakly with apo(a) (K(D) > 50 microM). Treatment of Glu(1)-plasminogen with citraconic anhydride (a lysine modification reagent) completely abolished binding to wild-type 17K r-apo(a), whereas citraconylated 17K r-apo(a) decreased binding to wild-type Glu(1)-plasminogen by approximately 50%; inhibition of binding was also observed using the lysine analogue epsilon-aminocaproic acid. Whereas native Glu(1)-plasminogen exhibited monophasic binding to 17K r-apo(a), truncated Lys(78)-plasminogen exhibited biphasic binding. Altering Glu(1)-plasminogen from its native, closed conformation (in chloride buffer) to an open conformation (in acetate buffer) also yielded biphasic isotherms. These SPR data are consistent with a two-state kinetic model in which a conformational change in the plasminogen-apo(a) complex may occur following the initial binding event. Differential binding kinetics between Glu(1)-/Lys(78)-plasminogen and apo(a) may explain why Lp(a) is a stronger inhibitor of tPA-mediated Glu(1)-plasminogen activation compared to Lys(78)-plasminogen activation.

Animals↗
PubMed1988

Characterizing hereditary and acquired defects of plasminogen.

Since plasminogen is the proenzyme of plasmin most acquired defects of plasminogen are associated with situations with an increased fibrinolytic activity. Congenital defects also have been described both such associated with thrombotic disease and such that are not. An increased fibrinolytic activity leading to an acquired plasminogen defect is seen 1) in situations complicated with a free proteolytic activity most often involving both the fibrinolytic and the coagulation systems, 2) as a result of locally increased fibrinolytic activity (angiomas), 3) during thrombolytic therapy using plasminogen activators (SK, UK, tPA). A congenital plasminogen defect characterized by 1) a low protein level as well as one with 2) a normal plasminogen protein level in plasma but a defect activation pattern has been reported. Plasminogen can be determined immunochemically, a method which does not differentiate between functionally active plasminogen/plasmin and complexes between these proteins and inhibitors. Plasminogen activity is measured in a chromogenic method using the chromogenic substrate S2251 (Kabi Diagnostica, Stockholm). In this latter method SK is used as a plasminogen activator and the total plasmin formed is measured amidolytically. Using both the immunochemical and the amidolytical methods it has been possible to identify congenital plasminogen defects characterized by a defective activation of plasminogen into plasmin, a defect that has been associated with thromboembolic disease. Another congenital plasminogen defect seems to be caused by a decreased synthesis of a normal plasminogen molecule. Such a defect may not be associated with thrombotic disease. In situations complicated with an increased fibrinolytic activity, decreased plasminogen levels (in both types of assay) are of diagnostic help. Values down to below 50% or even lower may be seen.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Coagulation Disorders↗
PubMed1989

Comparison of human normal, full-term, fetal and adult plasminogen by physical and chemical analyses.

Human fetal plasminogen was isolated from fetal cord blood obtained from full-term normal newborns. Two fetal plasminogen preparations were characterized by physical analyses and compared to adult human Glu-plasminogen. The protein concentration of plasminogen in each full-term fetal plasma was approximately 50% of the concentration found in adult plasma. The specific activity of the isolated plasminogen from both full-term fetal plasmas was 28.8 +/- 1.5 IU/mg protein, approximately the same as that of adult Glu-plasminogen. No significant difference was observed in the rate at which plasmin was generated from the normal fetal plasminogen and the adult Glu-plasminogen using streptokinase, urokinase, and tissue plasminogen activator. Electrophoretic analyses in an acrylamide gel/sodium dodecyl sulfate dissociating system showed that the fetal plasminogens and the adult Glu-plasminogen were the same molecular size. Analyses in an acrylamide gel isoelectric focusing system indicated that fetal and adult plasminogen both contained the same twelve isoelectric forms, however, there was a slight difference in the distribution of the isoelectric forms. The fetal and adult plasminogens both contained 792 +/- 1 amino acid residues, and there were no significant differences in amino acid composition between the fetal and adult preparations. These comparisons indicate that normal, full-term, fetal and adult Glu-plasminogen are identical.

Adult↗
PubMed1972

Plasminogen- 125 I responses in dogs to a single injection of urokinase and typhoid vaccine and to vascular injury.

In vivo plasminogen responses to various stimuli were studied. Plasminogen-(125)I was prepared and used first for metabolic studies of plasminogen in control dogs. The average results were: the plasma plasminogen, 29.3+/-4.1 (SD) mg/kg; the interstitial plasminogen, 8.79+/-4.47 (SD) mg/kg; the half-life of plasma plasminogen-(125)I, 2.81+/-0.24 (SD) days; the fractional direct catabolic rate of plasminogen (j(3)), 0.295 day(-1); and the catabolic (synthetic) rate of plasminogen, 8.61+/-1.35 (SD) mg/kg per day. Studies were then made of the plasminogen-(125)I responses in dogs to a single injection of urokinase (A) and typhoid vaccine (B), and to vascular injury (C), which was produced by the damage of venous endothelium by a phenol injection. Effects of heparin were also studied in dogs given the phenol injection (D). Disc electrophoretic analysis of plasma showed generation of plasmin-(125)I in all except the control experiments. The duration of plasmin-(125)I generation was about 6 hr in A, 6 hr in B, and at least 5 days in C. Heparinization (D) shortened the duration of generation to about 6 hr. For further quantitative analysis of the tracer data, a model for coexistent plasminogen-(125)I and plasmin-(125)I was proposed and validated, from which some new analytical methods were derived. Using these methods, the average fractional rate of plasmin-(125)I generation from plasminogen-(125)I (j(4)) was 0.41 day(-1) in A, 0.30 day(-1) in B, 0.324 day(-1) in C, and 0.382 day(-1) in D. Further mathematical consideration showed that j(3) was zero at least in C during plasmin generation. Plasminogen synthesis was unchanged in all experiments. The average fractional breakdown rate of plasmin-(125)I (j(5)) in A, B, C, and D was 1.19, 1.13, 1.35, and 1.11 day(-1), respectively, and were closely similar. These results indicate that under normal conditions a major portion of plasminogen is directly catabolized without the formation of plasmin, but that significant amounts of plasmin were generated under the conditions described, that the normal process of direct breakdown of plasminogen is abolished during plasmin generation at least in C, and that the potential value of j(5) determination should be further explored.

Animals↗
PubMed1996

Targeting of antibody-conjugated plasminogen activators to the pulmonary vasculature.

Thrombolytic therapy has not been widely used for pulmonary embolism due to less than optimal results with conventional plasminogen activators. We propose a new approach to deliver plasminogen activators to the luminal surface of the pulmonary vasculature to potentially improve dissolution of pulmonary thromboemboli. Our previous studies have documented that a monoclonal antibody (mAb) to angiotensin-converting enzyme (anti-angiotensin-converting enzyme mAb 9B9) accumulates in the lungs of various animal species after systemic administration. We coupled 125I-labeled biotinylated plasminogen activators (single-chain urokinase plasminogen activator, tissue-type plasminogen activator and streptokinase) to biotinylated mAb 9B9, using streptavidin as a cross-linker. The fibrinolytic activity of plasminogen activators was not changed significantly by either biotinylation or by coupling to streptavidin. Antibody-conjugated plasminogen activators bind to the antigen immobilized in plastic wells and provide lysis of fibrin clots formed in these wells. Therefore, antibody-conjugated plasminogen activators bound to their target antigen retain their capacity to activate plasminogen. One hour after i.v. injection of mAb 9B9-conjugated radiolabeled biotinylated single-chain urokinase plasminogen activator, biotinylated tissue-type plasminogen activator or biotinylated-streptokinase in rats, the level of radiolabel was 7.4 +/- 0.8, 5.9 +/- 0.4 and 3.6 +/- 0.4% of injected dose/g (ID/g) of lung tissue vs. 0.5 +/- 0.01, 0.3 +/- 0.01 and 0.6 +/- 0.3% ID/g after injection of the same activators conjugated with control mouse IgG (P < .01 in all cases). Injection of mAb 9B9-conjugated radiolabeled plasminogen activator led to its rapid pulmonary uptake with a peak value 6.2 +/- 1.2% ID/g attained 3 hr after injection. One day later, 2.2 +/- 0.5% of the injected radioactivity was found per gram of lung tissue, although the blood level was 0.13 +/- 0.03% ID/g (lung/blood ratio 16.7 +/- 0.3). Therefore, conjugation of plasminogen activators with anti-angiotensin-converting enzyme mAb 9B9 provides their specific targeting to and prolonged association with the pulmonary vasculature. These results provide a basis for study of the local pulmonary fibrinolysis by mAb 9B9-conjugated plasminogen activators.

Animals↗
PubMed1996

Plasminogen activator system: implications for mammary cell growth and involution.

Several tissue remodeling events that require extracellular proteolysis are thought to be mediated by plasminogen activators that convert the inactive proenzyme plasminogen to active plasmin. The involvement of plasminogen activator in many biological phenomena reflects the ubiquitous presence of plasminogen and the ability of numerous cell types to synthesize plasminogen activator in a highly regulated manner. Increased plasmin and plasminogen activator in bovine milk are correlated with gradual involution (the declining phase of lactation). Treatment with bST prevented the increase in plasmin during gradual involution, indicating that bST interferes with conversion of plasminogen to plasmin. Concentrations of plasminogen activator in mammary tissue are high after cessation of milking. These results reinforce the association of the plasmin-plasminogen system with gradual involution postlactation. Recently, a role has been proposed for plasminogen activator in cell proliferation in several cellular systems. Insulin and IGF-I increased synthesis of urokinase plasminogen activator and enhanced proliferation of cultured bovine mammary epithelial cells. In contrast, phorbol myristate acetate, which increased expression of urokinase plasminogen activator mRNA by mammary epithelial and myoepithelial cells, stimulated proliferation of myoepithelial cells, but not epithelial cells. Thus, expression of plasminogen activator is not simply related to mitogenesis but is likely to serve multiple functions in bovine mammary epithelial cells.

Animals↗
PubMed1991

Identification of an endothelial cell surface protein that binds plasminogen.

To identify and characterize endothelial cell surface components that bind plasminogen, we used ligand-blotting to study binding of plasminogen to sodium dodecyl sulphate solubilized extracts of human umbilical vein endothelial cells. It was observed that glu-plasminogen bound predominantly to a 45 kDa endothelial cell polypeptide. The interaction of labelled glu-plasminogen with this polypeptide was reversible and specific as the binding could be inhibited by both excess cold lysine and unlabelled glu-plasminogen but not by unrelated proteins. Binding of glu-plasminogen to cell extracts prepared from endothelial cells that had been pretreated with proteinase K was significantly reduced indicating that the 45 kDa polypeptide is a cell-surface protein. The cell-surface localization of the 45 kDa polypeptide was also indicated by the positive interaction of glu-plasminogen with membrane fractions of endothelial cells. Lys-plasminogen also interacted with the 45 kDa polypeptide in a specific manner and reversibility experiments indicated that lys-plasminogen could also displace the bound glu-plasminogen. Since binding of plasminogen to the 45 kDa endothelial cell surface polypeptide was very similar to plasminogen binding to intact endothelial cells, we propose that the 45 kDa protein represents one of the major receptors for plasminogen on human endothelial cells.

Cells, Cultured↗
PubMed1993

Effect of the nephritogenic autoantibody of Heymann's nephritis on plasminogen-binding to gp330 and activation by urokinase.

Previous results have shown that the autoantibody eluted from the glomeruli of rats with active Heymann nephritis contain a population of antibodies not only to the putative autoantigen of the disease, gp330, but also to plasminogen. Since gp330 has been shown to serve as a receptor for plasminogen, we have analyzed the effects of autoantibody on plasminogen-binding to gp330 and activation of plasminogen to plasmin by urokinase. Autoantibody does not inhibit the binding of plasminogen to gp330. The binding of autoantibody to plasminogen was shown to be very specific for the compact conformation of glu-plasminogen. The change in the conformation of plasminogen when its lysine-binding sites are occupied or after conversion to plasmin results in a significant decrease in autoantibody-binding. The most significant effect of autoantibody on this system is the inhibition of plasminogen activation to plasmin by urokinase. The binding of autoantibody to plasminogen acts as a competitive inhibitor of the reaction by apparently blocking access of urokinase to plasminogen's activation site. These results indicate that autoantibody obtained from the immune deposits in the glomeruli of rats with active Heymann nephritis does not inhibit the binding of plasminogen to gp330 but does significantly alter the urokinase catalyzed activation of plasminogen to plasmin.

Animals↗
PubMed2003

FTIR determination of ligand-induced secondary and tertiary structural changes in bovine plasminogen.

Human plasminogen undergoes a large tertiary structural change in the presence of lysine derivatives (e.g. epsilon-amino caproic acid, EACA). This change facilitates human plasminogen activation by human plasminogen activators, resulting in elevated blood plasmin levels. It is hypothesized that this structure-function relationship is similar for bovine plasminogen. The objectives of this study were to investigate the effect of the ligand EACA on the secondary structure of plasminogen (bovine, human, and rabbit) and the tertiary structure of bovine plasminogen using Fourier-transform infrared spectroscopy (FTIR). Spectra of plasminogen, EACA, and a mixture of plasminogen and EACA in water and deuterium were collected using FTIR. Fourier-self deconvoluted spectra in the amide I region (1700-1600 cm(-1)) were used to detect changes in secondary structure of plasminogen after EACA addition. Change in bovine plasminogen tertiary structure was determined by comparing ratios of amide II (1600-1500 cm(-1)) to amide I bond intensities over time for samples in deuterium. No differences in secondary structure were observed for any plasminogen in the presence of EACA; however, addition of EACA significantly changed tertiary structure of bovine plasminogen. This tertiary structural change indicates a transition from a folded to an unfolded state, which could be more easily converted to plasmin. These results are consistent with reported human plasminogen studies using neutron scattering (tertiary structure) and circular dichroism (secondary structure) methods.

Aminocaproic Acid↗
PubMed1989

The effects of plasminogen on in vitro ovine embryo development.

Plasminogen activator production by ovine embryos and the effects of plasminogen on ovine embryo development and zona pellucida integrity were evaluated. Eight-cell to sixteen-cell embryos were cultured in Whitten's medium containing 0, 60, or 120 micrograms/ml plasminogen. Plasmin and plasminogen activator concentrations in the medium were determined by a caseinolytic assay. More blastocysts hatched in medium containing 60 and 120 micrograms/ml plasminogen (33 and 21%, respectively) than 0 microgram/ml plasminogen (0%; p less than 0.05). Zona pellucida dissolution time in acidified phosphate-buffered saline was less after incubation in medium with 60 and 120 micrograms/ml plasminogen (7.2 and 5.9 min, respectively) than 0 microgram/ml plasminogen (9.4 min; p less than 0.05). Plasminogen activator production was low until the morula stage, increased during morula-blastocyst transition, and remained elevated through blastocoelic expansion and hatching. Zona pellucida solubility, plasminogen activator production, and plasminogen conversion to plasmin increased as embryonic stage advanced; however, plasminogen activator production and plasmin conversion to plasmin were poorly correlated with zona pellucida solubility. The results indicate that ovine embryos produce plasminogen activator, and plasmin can increase zona pellucida solubility; however, other factors may also be involved in altering zona pellucida integrity prior to hatching.

Animals↗
PubMed2004

Prion protein stimulates tissue-type plasminogen activator-mediated plasmin generation via a lysine-binding site on kringle 2.

Recombinant human prion-protein (PrP23-231) stimulates plasminogen activation by tissue-type plasminogen activator (t-PA). The stimulatory activity is conserved in the N-terminal fragment (PrP23-110). It has further been shown by others that PrP(c) binds to kringle-domains of plasminogen. We compared the stimulatory activity of recombinant PrP23-231 and PrP23-110 on plasminogen activation catalyzed by t-PA, urokinase (u-PA), streptokinase and Desmodus salivary plasminogen activator (DSPAalpha1). As these plasminogen activators are distinct, with respect to their kringle domains we studied their binding to immobilized PrP23-110. Plasminogen activation was measured in a chromogenic assay in vitro and binding studies were carried out using surface plasmon resonance technology. We found that recombinant full-length prion protein, PrP23-231, and PrP23-110 specifically stimulate t-PA mediated plasminogen activation. Two hundred nanomoles per liter of PrP23-110 stimulated 1.8 nmol L(-1) t-PA 48-fold, 180 nmol L(-1) DSPA(alpha1) 2.5-fold, 1.8 nmol L(-1) u-PA 1.1-fold, and 1.8 nmol L(-1) streptokinase 1.8-fold. Our data show no specific binding for streptokinase. In contrast all plasminogen activators carrying a kringle domain bound to PrP23-110. We further studied the effect of lysine on binding to PrP23-110 and on plasminogen activation by DSPA(alpha1) or t-PA. Lysine decreased both the binding of t-PA to PrP23-110 and the stimulation of plasmin generation by t-PA. Both binding and plasminogen activation of DSPA(alpha1) were not influenced by the presence of lysine. All plasminogen activators tested bearing kringle domains bind to PrP23-110. Binding to PrP23-110 is not sufficient for stimulation of plasmin generation. Thus the lysine-binding site of kringle 2 that is unique to t-PA appears to mediate the specific stimulation of plasminogen activation by the cellular prion protein.

Binding Sites↗
PubMed1998

Plasminogen binding and activation at the surface of Helicobacter pylori CCUG 17874.

The binding of iodine-labelled plasminogen to Helicobacter pylori CCUG 17874 was characterized. Inhibition of the binding was observed after preincubation of H. pylori cells with nonradiolabelled plasminogen, lysine, or the lysine analogue epsilon-aminocaproic acid. Fragments of plasminogen, kringles 1 to 3, kringle 4, and mini-plasminogen, were also studied as potential inhibitors. Mini-plasminogen caused total inhibition of the plasminogen binding, while the other fragments caused only partial inhibition. These findings suggest that H. pylori binds specifically the fifth kringle structure of the plasminogen molecule. Plasminogen binding to H. pylori seems to be independent of culture media and independent of the presence of the cytotoxin-associated CagA antigen. Immunoblot analysis identified two plasminogen binding proteins of 57 and 42 kDa. Scatchard plot analysis revealed one binding mechanism with a Kd value of 7 x 10(-7) M. Conversion of H. pylori cell-bound plasminogen to plasmin in the presence of a tissue-type plasminogen activator was demonstrated by digestion of the chromogenic substrate S-2251. No activation was noted when plasminogen or tissue-type plasminogen activator was incubated with H. pylori cells alone. Formation of H. pylori cell surface-bound plasmin may be important to provide a powerful proteolytic mechanism for gastric tissue penetration in type B gastritis and peptic ulcer disease, since plasmin degrades not only fibrin but also extracellular matrix proteins such as various collagens and fibronectin.

Aminocaproic Acid↗
PubMed1985

Binding and activation of plasminogen on the platelet surface.

A mechanism by which platelets might participate in fibrinolysis by binding plasminogen and influencing its activation has been examined. Binding of radioiodinated human Glu-plasminogen to washed human platelets was time-dependent and was enhanced 3-9-fold by stimulation of platelets with thrombin but not with ADP. The interaction with both stimulated and unstimulated cells was specific, saturable, divalent ion-independent, and reversible. The platelet-bound ligand had the molecular weight of plasminogen, and no conversion to plasmin was detected. Scatchard analyses provided evidence for a single class of plasminogen-binding sites on both stimulated and unstimulated cells. The Kd for thrombin-stimulated platelets was 2.6 +/- 1.3 microM, and 190,000 +/- 45,000 molecules were bound per cell, whereas unstimulated platelets bound 37,000 +/- 10,500 molecules/cell with a Kd of 1.9 +/- 0.15 microM. Plasminogen binding was inhibited in a dose-dependent manner by omega-aminocarboxylic acids at concentrations consistent with a requirement for an unoccupied high affinity lysine-binding site for plasminogen binding to the cells. When platelet-bound plasminogen was incubated with tissue plasminogen activator, urokinase, or streptokinase, gel analysis established that plasmin was preferentially associated with the platelet relative to the supernatant. Plasminogen and plasmin interacted with thrombin-stimulated platelets with similar binding characteristics, and there was no evidence for a binding site for plasmin which did not also bind plasminogen. Therefore, the results suggest that plasminogen activation is enhanced on the cell surface. In sum, these results indicate that platelets bind plasminogen at physiologic zymogen concentrations and this interaction may serve to localize and promote plasminogen activation.

Adenosine Diphosphate↗
PubMed2000

Effects of a fucoidan on the activation of plasminogen by u-PA and t-PA.

The effect of an anticoagulant fucoidan (C-I-H) from the brown seaweed Ecklonia kurome on the fibrinolytic system was studied in vitro using S-2251 as a substrate of plasmin. C-I-H enhanced the activation of Glu- and Lys-plasminogen by high molecular weight urokinase-type plasminogen activator (HMW u-PA) very effectively, but the activation by low molecular weight u-PA was hardly enhanced with C-I-H. C-I-H also potentiated moderately the activation by single- and two-chain tissue-type plasminogen activators (sct- and tct-PA). These effects of C-I-H were higher than those of heparin used. But C-I-H had no effect on the amidolytic activity of plasmin to S-2251. These results indicate that C-I-H promotes the generation of plasmin in the plasminogen activation by HMW u-PA and t-PA, but not the activity of generated plasmin. Kinetic analyses suggest that C-I-H enhances the HMW u-PA-mediated plasminogen activation by increasing the affinity of the activator for Glu- and Lys-plasminogen and by increasing the molecular activity of the activator. On the other hand, C-I-H had no effect on the affinity of tct-PA for both plasminogens. The catalytic efficiencies of HMW u-PA and tct-PA for the activation of both plasminogens were increased with C-I-H about 8- and 2-fold, respectively. The present results suggest that C-I-H has the fibrinolytic activity by stimulating the plasminogen activation by HMW u-PA and t-PA. The mechanism of the enhancement effect of C-I-H on the activation is presumed to be that C-I-H binds to plasminogen, thereby inducing a structural change of plasminogen susceptible to the action of plasminogen activators.

Anticoagulants↗
PubMed1984

Interference of active site specific reagents in plasminogen-streptokinase active site formation.

We have recently observed slow, non-Michaelis-Menten kinetics of activation of native cat plasminogen by catalytic concentrations of streptokinase. In order to understand the reasons for this phenomenon, we undertook to study the formation of the plasminogen-streptokinase activator complex under the same plasminogen activation conditions. The results obtained in this study show that the potential active site in both cat and human plasminogen is capable of binding strongly the specific substrates (S) p-nitrophenyl p-guanidinobenzoate (NPGB) and H-D-valyl-L-leucyl-L-lysyl-p-nitroanilide, through the active site is incapable of hydrolyzing these substrates. Binding studies support these and the following conclusions. Streptokinase binds to this zymogen-substrate complex to create the ternary plasminogen-S-streptokinase complex, which then slowly converts to an acylated plasminogen-streptokinase form. This acylation reaction is 550 times slower than acylation of the preformed plasminogen-streptokinase complex by NPGB. The same reaction also occurs with human plasminogen, though the acylation reaction is 10 times faster than when the cat zymogen is used. NPGB binds specifically to plasminogen but not to streptokinase. These studies proved that inhibition of cat plasminogen activation by streptokinase occurs at the level of activator complex formation. We conclude from our studies that streptokinase binding to both cat and human plasminogen occurs at the potential active site of the zymogen. Consequently, it is probable that plasminogen activation in vivo is inhibited by binding of active site specific inhibitors to plasminogen.

Acylation↗