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PubMed2002

Increased migration of murine keratinocytes under hypoxia is mediated by induction of urokinase plasminogen activator.

One of the key consequences of cutaneous wounding is the development of tissue hypoxia. Recent data have suggested that this is a potent stimulus for increased keratinocyte migration and hence re-epithelialization, although the mechanisms responsible for this remain unclear. In this study we have investigated the relationship between hypoxia, plasminogen activation, and in vitro wound healing. Exposure of keratinocyte cultures to hypoxia resulted in upregulation of urokinase plasminogen activator mRNA and a subsequent increase in urokinase plasminogen activator-mediated plasminogen activation, as determined by indirect chromogenic peptide assay and plasminogen-linked zymography. Analysis of keratinocyte wound healing in vitro confirmed enhanced wound closure in hypoxic cultures compared with normoxic cultures after 16 h. Pretreatment of normoxic and hypoxic cultures with mitomycin C and cytochalasin B indicated that in this system wound closure was due to keratinocyte migration rather than proliferation. Addition of the broad-spectrum serine proteinase inhibitor, p-aminobenzamidine, or the specific urokinase plasminogen activator inhibitors, amiloride and WX-293, significantly reduced wound closure in hypoxic cultures and abrogated the hypoxic enhancement of wound closure. These data indicate a central role for urokinase plasminogen activators in hypoxic keratinocyte migration and suggest a potential mechanism for enhanced re-epithelialization of wounds under low oxygen tensions.

Animals↗
PubMed2004

Plasminogen is tethered with high affinity to the cell surface by the plasma protein, histidine-rich glycoprotein.

Plasminogen has been implicated in extracellular matrix degradation by invading cells, but few high affinity cell surface receptors for the molecule have been identified. Previous studies have reported that the plasma protein, histidine-rich glycoprotein (HRG), interacts with plasminogen and cell surfaces, raising the possibility that HRG may immobilize plasminogen/plasmin to cell surfaces. Here we show, based on optical biosensor analyses, that immobilized HRG interacts with soluble plasminogen with high affinity and with an extremely slow dissociation rate. Furthermore, the HRG-plasminogen interaction is lysine-dissociable and involves predominately the amino-terminal domain of HRG, and the fifth kringle domain of plasminogen, but not the carboxyl-terminal lysine of HRG. HRG was also shown to tether plasminogen to cell surfaces, with this interaction being potentiated by elevated Zn(2+) levels and low pH, conditions that prevail at sites of tissue injury, tumor growth, and angiogenesis. Based on these data we propose that HRG acts as a soluble adaptor molecule that binds to cells at sites of tissue injury, tumor growth, and angiogenesis, providing a high affinity receptor for tethering plasminogen to the cell surface and thereby enhancing the migratory potential of cells.

Angiostatins↗
PubMed1995

Differential effects of staphylokinase, streptokinase and tissue-type plasminogen activator on the lysis of retracted human plasma clots and fibrinolytic plasma parameters in vitro.

A novel plasma clot lysis system was used to compare the fibrinolytic characteristics of staphylokinase, streptokinase and tissue-type plasminogen activator. 125I-fibrinogen-labelled human plasma clots were formed on needles and mechanically compressed after spontaneous retraction. This model is relatively resistant to lysis and differentiates between fibrin-specific and non-fibrin-specific plasminogen activators. The novel plasminogen activator, recombinant staphylokinase, produced high rates of clot lysis without markedly influencing fibrinogen, plasminogen and alpha 2-antiplasmin in the plasma containing the clots. At equimolar concentrations, streptokinase markedly depleted these parameters in plasma despite low clot lysis rates. Tissue-type plasminogen activator showed relatively high lysis rates at low concentrations, but at higher concentrations, plasminogen depletion caused a decrease in clot lysis. Staphylokinase can be characterised as a fibrin-specific and plasminogen-saving fibrinolytic agent with a high clot lysis potential.

Fibrinogen↗
PubMed1996

The use of intravitreal tissue plasminogen activator in the treatment of experimental subretinal hemorrhage in the pig model.

PURPOSE: To clinically and surgically evaluate clot lysis in an animal model of subretinal hemorrhage after intravitreal injection of tissue plasminogen activator. METHODS: Autologous subretinal hemorrhages were created via a transvitreal approach in 18 pigs. The next day (day 1) animals were randomly selected to receive either an intravitreal injection of 0.1 mL balanced salt solution or 0.1 mL tissue plasminogen activator (25 micrograms) followed by observation or vitrectomy a day later. On day 2, six pigs (all treated with tissue plasminogen activator) underwent a vitrectomy in which aspiration of the subretinal hemorrhage was attempted. The other eyes were evaluated for clot lysis by ophthalmoscopy at days 3, 10, and 30. All eyes were examined histopathologically. RESULTS: The eyes that had been treated with tissue plasminogen activator demonstrated a color change at the peripheral margin, which suggested that clot lysis had occurred. At the time of the vitrectomy, the clots were liquefied partially; removal by aspiration alone, however, was not possible. Photoreceptor damage was moderate to severe by day 10 in all eyes, whether they were treated with tissue plasminogen activator or balanced salt solution. All eyes that underwent vitrectomy had moderate to severe photoreceptor damage. CONCLUSIONS: In this animal model, intravitreal tissue plasminogen activator was associated with features that suggested partial clot lysis; tissue plasminogen activator did not produce sufficient lysis to allow surgical removal by aspiration alone, however.

Animals↗
PubMed1987

Involvement of urokinase-type plasminogen activator in acantholysis induced by pemphigus IgG.

Pemphigus IgG induces acantholysis in skin organ culture without the involvement of complement. Urokinase-type plasminogen activator, a proteolytic enzyme, has been implicated in the development of acantholysis. To test this hypothesis, we prepared a rabbit anti-urokinase antibody, which inhibited the plasminogen activator activity in normal human epidermis and in cultured keratinocytes. When added to skin organ cultures along with pemphigus IgG, anti-urokinase IgG completely prevented the development of acantholysis. Normal or preimmune rabbit IgG had no effect on pemphigus IgG-induced acantholysis. Plasminogen activator converts the zymogen plasminogen to its active form plasmin, a broad specificity serine proteinase. When high concentrations of plasminogen alone were added to skin organ culture, acantholysis of the pemphigus foliaceous type was induced. Anti-urokinase antibody also inhibited plasminogen-induced acantholysis. These results strongly support a pivotal role for plasminogen activator in the development of acantholysis.

Acantholysis↗
PubMed1984

Enhanced fibrinolytic activity during cardiopulmonary bypass in open-heart surgery in man is caused by extrinsic (tissue-type) plasminogen activator.

The nature of the enhanced blood fibrinolytic activity which is known to occur during cardiopulmonary bypass is not understood. We show here that the cause is an increase in extrinsic (tissue-type) plasminogen activator. In six patients, the nature of the enhanced blood fibrinolytic activity that evolved during cardiopulmonary bypass was characterized by differential inhibition using the fibrin plate method and was shown to be C1-inactivator-resistant (extrinsic-activator activity). The C1-inactivator-resistant-activator activity was completely quenched by an antibody against extrinsic (tissue-type) plasminogen activator but not by antiurokinase, proving that the activity was due to the presence of extrinsic (tissue-type) plasminogen activator. The concentration of extrinsic (tissue-type) plasminogen activator increased during cardiopulmonary bypass and disappeared rapidly thereafter. Fibrinogen, plasminogen and alpha 2-antiplasmin were not consumed during cardiopulmonary bypass, while no increase or occasionally a moderate one in fibrinogen degradation products occurred. This is in accord with the property of extrinsic (tissue-type) plasminogen activator which activates plasminogen predominantly at sites where fibrin is present and not in the free circulation.

Cardiopulmonary Bypass↗
PubMed1988

Binding of tissue-type plasminogen activator to fibrinogen fragments.

In order to localize the binding site(s) for tissue-type plasminogen activator (t-PA) in the fibrin(ogen) molecule, the following binding assay was developed. Two-chain t-PA was immobilized onto microtitration plates. The t-PA-coated plates were then incubated with fibrinogen and various fibrinogen fragments. The extent of binding was quantified with enzyme-labelled antibodies against fibrin(ogen) and its fragments. Hardly any binding to t-PA was observed with fibrinogen or fragments X, Y and E; a moderate binding was observed with fragments Dcate and DEGTA and a strong binding with the cyanogen bromide fragment FCB-2 (Kd apparent = 140 nM). The binding of fibrinogen and its fragments to immobilized Lys-plasminogen was measured by the same method as a control for the binding assay. Results were in line with literature data: virtually no binding to Lys-plasminogen with fibrinogen or fragments X and Y, a moderate binding with fragments Dcate, DEGTA and E and a strong binding with FCB-2 (Kd apparent = 70 nM). The stimulatory capacity of the various fragments on the Lys-plasminogen activation by t-PA, as studied in a spectrophotometric assay, was found to be absent for fragment E, low for fibrinogen, fragments X, Y, Dcate and DEGTA, and high for FCB-2. It is concluded that a t-PA-binding site resides in the C-terminal globular domains of fibrinogen from which fragments D and FCB-2 originate. The site is hidden in the native fibrinogen molecule and in early fibrinogen degradation products. Binding of both Lys-plasminogen and t-PA appears to be required for a stimulator of the plasminogen activation, as illustrated by fragment E which only binds Lys-plasminogen and has no stimulatory capacity.

Binding Sites↗
PubMed1989

New receptor for human plasminogen on gram positive cocci.

180 bacterial strains representing 17 different species of gram positive cocci were tested for the ability to interact with human plasminogen. Receptors for plasminogen could be detected on 23/24 strains of S. pyogenes, 15/15 strains of S. equisimilis, 14/16 strains of human group G streptococci and 14/14 strains of S. pneumoniae. Eight of nineteen strains representing five species of alpha-hemolytic streptococci were also positive. S. equisimilis demonstrated the highest uptake with a median value of 58 per cent (20%-67%). On the other hand, all strains of S. agalactiae, the majority of S. faecalis and all S. aureus, S. epidermidis and S. saprophyticus strains tested were negative. The concentration of unlabelled plasminogen causing a 50 per cent reduction of bound tracer was between 50 and 150 mM. These estimates of the dissociation constant confirmed the specific nature of the interaction. Binding of plasminogen could be blocked by addition of plasmin-aprotinin complex, suggesting that plasminogen and plasmin bind to the same receptor. Binding was also blocked by the plasminogen fragment kringle 1-3, but not by miniplasminogen, a fragment containing kringle 5 and the B-chain region. As streptokinase interacts mainly with the B-chain of plasmin it is clear that the bacterial receptor for plasminogen is not identical to streptokinase.

Animals↗
PubMed1977

Activation of plasminogen as a feature in its assay.

Seven laboratories collaborating in a study of two intermediate purity plasminogen preparations (64/23, 63/6) observed that the amount of activator (urokinase or streptokinase) and the time of activation of plasminogen influenced the amount of plasmin generated. Using casein and a synthetic polypeptide (S-2251) as substrates, the authors subsequently showed that complete activation of plasminogen was difficult to achieve without acitivity losses due to plasmin autodigestion. Comparison of the polypeptide subunits (on SDS electrophoresis) of the various plasminogen activation mixtures with their plasmin activity allowed the conclusion that at maximum generation of plasmin from plasminogen, some plasminogen remains in the form of an inactive plasminogen intermediate (PLG-i).

Caseins↗
PubMed1988

Reference values and variability of plasminogen in healthy blood donors and its relation to parameters of the fibrinolytic system.

During a survey of four month's duration the following parameters were determined in 43 healthy blood donors (22 males, 21 females; mean age 29 years/20-49/): plasminogen activity, plasminogen concentration, alpha 2-antiplasmin (alpha 2-AP) activity, alpha 2-AP concentration, tissue type plasminogen activator (t-PA) activity, t-PA concentration, plasminogen activator inhibitor--I (PAI-I) activity, AT III activity, AT III concentration and heparin cofactor II (HC II) activity. Normal values including standard deviation (x +/- 2s) were: plasminogen activity: 96.3% (65.9-126.8), plasminogen concentration: 12.2 mg/dl (7.7-16.8), alpha 2-AP activity: 99.9% (83.8-116), alpha 2-AP concentration: 108.1% (84.5-131.8), t-PA activity: 0.85 IU/l (0.0-1.92), t-PA concentration: 10.3 ng/ml (2.5-18.1), PAI-I activity: 15.2 AU/ml, AT III activity: 111.4% (87.8-134.9), AT III concentration: 31.6 mg/dl (24.2-39.1) and HC II activity: 110.7% (81.4-140.0). Concerning plasminogen values no sex related difference could be stated. Women who were smokers and used oral contraceptives tended to present elevated t-PA activity levels due to a lower activity of PAI-I, although this tendency was not significant. Determining concentration and activity of components in the fibrinolytic system plays an important part in the diagnosis, therapy and prognosis of thrombophilic disorders.

Adult↗
PubMed2004

Both lysine-clusters of the NH2-terminal prion-protein fragment PrP23-110 are essential for t-PA mediated plasminogen activation.

We have recently shown that the NH(2)-terminal fragment (PrP23-110) of the human cellular prion protein (PrP(c) ) stimulates t-PA mediated plasminogen activation. PrP23-110 contains an N-terminal lysine cluster (LC1; K(23),K(24), K(27)) and a C-terminal one (LC2; K(101),K(104),K(106),K(110)). To study their biological function we have substituted all lysine residues of each cluster by alanine and generated the recombinant PrP proteins PrP23-110sLC1 and PrP23-110sLC2. The ability of the mutant proteins to stimulate plasminogen activation was assayed. We found that both lysine clusters are essential for t-PA mediated plasminogen activation. We further studied the binding of soluble PrP23-110 to immobilized t-PA or plasminogen using surface plasmon resonance. The recorded binding curves could not be modeled by classical 1:1 binding kinetics suggesting oligomerisation of PrP23-110. Further plasmon resonance studies show that indeed PrP23-110 binds to itself and that glycosaminoglycans modify this interaction. Binding of t-PA or plasminogen to PrP23-110 was no longer influenced by glycosaminoglycans when PrP23-110 was immobilized on the chip surface. Thus a possible role of heparin as a cofactor in the stimulation of plasminogen activation by t-PA could be the generation of a PrP23-110 form with both lysine clusters accessible for binding of t-PA and plasminogen.

Blotting, Western↗
PubMed1992

The expression of tissue and urokinase-type plasminogen activators in neural development suggests different modes of proteolytic involvement in neuronal growth.

Tissue and urokinase-type plasminogen activators are serine proteases with highly restricted specificity, their best characterised role being to release the broad specificity protease plasmin from inactive plasminogen. It has frequently been suggested that these, and similar proteases, are involved in axonal growth and tissue remodelling associated with neural development. To help define what this role might be, we have studied the expression of the plasminogen activators in developing rat nervous tissue. Urokinase-type plasminogen activator mRNA is strongly expressed by many classes of neurons in peripheral and central nervous system. We have analysed its appearance in spinal cord and sensory ganglia, and found the mRNA is detectable by in situ hybridisation very early in neuronal development (by embryonic day 12.5), at a stage compatible with it playing a role in axonal or dendritic growth. Tissue plasminogen activator mRNA, on the other hand, is expressed only by cells of the floor plate in the developing nervous system, from embryonic day 10.5 and thereafter. Immunohistochemical and enzymatic analysis showed that active tissue plasminogen activator is produced by, and retained within, the floor plate. A mechanism is suggested by which high levels of tissue plasminogen activator produced by the stationary cells of the floor plate could influence the direction of growth of commissural axons as they pass through this midline structure.

Animals↗
PubMed2004

Plasminogen interaction with Trypanosoma cruzi.

The ability of Trypanosoma cruzi to interact with plasminogen, the zimogenic form of the blood serin protease plasmin, was examined. Immunohistochemistry studies revealed that both forms, epimastigotes and metacyclic trypomastigotes, were able to fix plasminogen in a lysine dependant manner. This interaction was corroborated by plasminogen activation studies. Both forms of the parasite enhanced the plasminogen activation by tissue-type plasminogen activator. The maximal enhancements obtained were 15-fold and 3.4-fold with epimastigotes and metacyclic trypomastigotes, respectively, as compared to plasminogen activation in absence of cells. Ligand-blotting analysis of proteins extracted with Triton X-114 from a microsomal fraction of epimastigotes revealed at least five soluble proteins and one hydrophobic protein able to bind plasminogen.

Animals↗
PubMed2000

Hormonal control of plasmin and tissue-type plasminogen activator activity in rat milk during involution of the mammary gland.

We have proposed that growth hormone (GH) and prolactin (PRL) interact to suppress apoptosis in the mammary gland. GH increases insulin-like growth factor-I (IGF-I) synthesis whereas PRL suppresses the production of insulin-like growth factor-binding protein-5 (IGFBP-5) in the epithelial cells, which would otherwise inhibit IGF-mediated cell survival. IGFBP-5 was present in milk from involuting glands at high concentrations (approximately 60 microg/ml) and had a high affinity (8.03 x 10(-10) M) for IGF-I, suggesting an inhibitory effect of IGFBP-5 in the mammary gland. IGFBP-5 was present in the micellar fraction of milk and binds specifically to alpha(s2)-casein. Since alpha(s2)-casein also binds plasminogen and tissue-type plasminogen activator (t-PA), resulting in the conversion of plasminogen to plasmin, and since IGFBP-5 binds to plasminogen activator inhibitor-1 (PAI-1), we investigated whether apoptosis and extracellular matrix (ECM) degradation might be coordinately controlled by GH and PRL possibly acting through IGFBP-5. Litters were removed from lactating rats to initiate involution. Plasminogen activation and t-PA activity were both increased dramatically after 48 h and GH and PRL suppressed this response. By contrast, 17beta-oestradiol, progesterone or corticosterone did not influence either process. An antiserum to IGF-I, which blocked systemic IGF-I effects, failed to inhibit the activation of plasminogen or the increase in t-PA, suggesting that paracrine effects of IGF-I may be more important. Teat-sealing, which led to the accumulation of milk without hormonal changes, also led to increases in plasminogen activation and t-PA activity, suggesting that locally produced factors (of which IGFBP-5 is one) are important in controlling ECM remodelling. We propose that GH and PRL inhibit apoptosis and ECM remodelling by a process that involves the control of IGF-I and PAI-1 availability by IGFBP-5, thus allowing these processes to be tightly coordinated.

Animals↗
PubMed2004

Effects of native and denatured whey proteins on plasminogen activator activity.

The plasmin system native to bovine milk consists of the caseinolytic serine proteinase plasmin; its inactive zymogen, plasminogen; plasminogen activators; and inhibitors. Evidence in the literature indicates that whey proteins may inhibit plasmin activity, but there is very little mention of their effect on plasminogen activators. The objective of this research was to determine the effect of both unheated and heat-denatured beta-lactoglobulin (beta-LG), alpha-lactalbumin (alpha-LA), and BSA on plasminogen activators. Plasminogen activator activity was significantly stimulated by non-heat treated and denatured alpha-LA as well as by denatured beta-LG. The stimulation effect by these whey proteins was kinetically characterized, which showed that all 3 significantly increased the rate of plasminogen activation. The stimulation effect was shown to be independent of any effect of the whey proteins on plasmin activity by testing 2 different substrates, d-Val-Leu-Lys p-nitroanilide (S-2251) and Spectrozyme PL (Spec PL), in a plasmin assay. Results using S-2251 confirmed the inhibitory effect of whey proteins on plasmin observed by several researchers. However, use of SpecPL did not suggest inhibition. Ligand binding studies showed this discrepancy to be due to significant interaction between S-2251 and the whey proteins. Overall, this study indicates that whey protein incorporation into cheese may not hinder plasmin activity and may stimulate plasminogen activation. Furthermore, the results indicate the need for careful consideration of the type of synthetic substrate chosen for model work involving whey proteins and the plasmin system.

Fibrinolysin↗
PubMed2000

The surface of prostate carcinoma DU145 cells mediates the inhibition of urokinase-type plasminogen activator by maspin.

Maspin is a novel serine protease inhibitor (serpin) with tumor suppressive potential in breast and prostate cancer, acting at the level of tumor invasion and metastasis. It was subsequently demonstrated that maspin inhibits tumor invasion, at least in part, by inhibiting cell motility. Interestingly, in cell-free solutions, maspin does not inhibit several serine proteases including tissue-type plasminogen activator and urokinase-type plasminogen activator (uPA). Despite the recent biochemical evidence that maspin specifically inhibits tissue-type plasminogen activator that is associated with fibrinogen or poly-L-lysine, the molecular mechanism underlying the tumor-suppressive effect of maspin remains elusive. The goal of this study was to investigate the effect of maspin on cell surface-associated uPA. In our experimental system, we chose prostate carcinoma DU145 cells because these cells mediate plasminogen activation primarily by uPA, as shown by two different colorimetric enzyme activity assays. Purified recombinant maspin produced in baculovirus-infected Spodoptera frugiperda Sf9 insect cells [rMaspin(i)] binds specifically to the surface of DU145 cells, inhibits the DU145 cell surface-bound uPA, and forms a stable complex with the uPA in DU145 cell lysate. The inhibitory effect of rMaspin(i) on cell surface-bound uPA was similar to that of an uPA-neutralizing antibody and was reversed by a polyclonal antibody against the reactive site loop sequence of maspin. The Ki value for rMaspin(i) in cell surface-mediated plasminogen activation was 20 nM, which was comparable to the Ki values for plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2, respectively. Furthermore, the proteolytic inhibitory effect of rMaspin(i) was quantitatively consistent with its inhibitory effect on the motility of DU145 cells in vitro. Our data demonstrate an important role for the prostate carcinoma cell surface in mediating the inhibitory interaction between rMaspin(i) and uPA. Thus, future maspin-based therapeutic strategies may prove useful in blocking the invasion and metastasis of uPA-positive prostate carcinoma.

Antineoplastic Agents↗
PubMed1978

[Releasing of plasminogen-activator from the kidney to the blood (author's transl)].

When fibrinolytic activity in blood samples from various vessels was examined by the dilute-blood-clotlysis-time method (DBCLT), it was found to be noticeably high in the renal venous blood, though the activity was not detected by usual blood clotlysis time method. Plasmin was not detected in any blood samples examined, and the contents of fibrinogen and fibrin (or fibrinogen) breakdown products in the renal venous blood were not significantly different from those in the blood from other vessels. However, the high activity of plasminogen-activator was found only in the renal venous blood. Inhibitors on plasmin and plasminogen-activator (urokinase) were detected in almost the same amount in the blood samples from the various vessels. The amount of the inhibitors was sufficient to inhibit the plasminogen activation by urokinase, whose activity was equivalent to the plasminogen-activator activity in the renal venous blood. These results indicate that the high activity by DBCLT in the renal venous blood was derived from the high activity of plasminogen-activator, which was inactivated by inhibitors in undiluted blood. Plasminogen-activator may be released from the kidney to the blood, and immediately inactivated by the inhibitors in renal vein, and then diluted with systemic blood which contains little plasminogen-activator.

Animals↗
PubMedDate not supplied

[Plasminogen activation by a tissue activator and effector properties of fibrinogen-N-terminal disulfide (N-DSK) fibrin complex].

Fibrinogen-NDSK complex is a model of protofibril having some features of the fibrin polymer structure. This complex has been studied for its ability to stimulate the plasminogen activation by t-PA. The fibrinogen-NDSK complex have increased the rate of plasminogen activation by t-PA as compared to fibrinogen or NDSK taken separately. This acceleration had slow and fast phases. Lys-plasminogen was activated more effectively as compared to glu-plasminogen. The kinetic parameters of glu- and lys-plasminogen activation at fast phase were: Km--0.18 and 0.015 mu/M, Kkat--0.27 and 0.06 s-1, respectively. Fibrinogen X2--fragments, deprived of alpha C-domains and NH2-end peptides of bB-chains, formed complexes with NDSK, which however did not stimulate the plasminogen activation by t-PA. These findings have shown that the fibrinogen-NDSK complex is an effective stimulator of the plasminogen activation by t-PA. The activating ability of the complex may be due to structures formed in the course of fibrinogen and NDSK polymerization as a result of alpha C-domain interaction.

Disulfides↗