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PubMed1993

Antigens of tissue plasminogen activator and plasminogen activator inhibitor 1: correlates in nonsmoking Japanese and Caucasian men and women.

We reported in a 1987 preliminary study that tissue plasminogen activator antigen was significantly higher in American Caucasian men than in Japanese men. To further examine possible differences in fibrinolytic activity between the two races, an expanded study was conducted in a total of 300 nonsmoking men and women aged 47-69 years in two population-based samples: rural Japanese living in Akita and Caucasians living in Minneapolis-St. Paul, MN. Antigens of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor 1 (PAI-1) were measured. Mean t-PA antigen was 2.3 ng/ml higher in Caucasian men than in Japanese men (P < 0.001), but no race difference was seen for women (P = 0.59). Mean PAI-1 was higher in Caucasians than in Japanese for both sexes, and the race difference in mean was 1.8 ng/ml for men (P = 0.07) and 4.4 ng/ml for women (P < 0.001). Both t-PA and PAI-1 were associated positively with body mass index and blood triglycerides for all sex-race groups, and positively with alcohol intake for Japanese and Caucasian men. Compared to Japanese, Caucasians of both sexes had higher levels of body mass index and blood triglycerides, and lower average intake of alcohol among men. Even when adjusted for body mass index, triglycerides, alcohol and other cardiovascular risk factors, the race difference in mean t-PA antigen persisted for men (P < 0.001), as did the difference in mean PAI-1 for men (P = 0.03) and women (P = 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1993

Evolution of urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen activator (t-PA) in orthotopic liver transplantation (OLT).

In orthotopic liver transplantation (OLT) hyperfibrinolysis seems to be of causative importance for intra- and postoperative bleeding. Although recently hyperfibrinolysis has been successfully reduced by intraoperative aprotinin treatment, small increases of fibrinolysis still remain during OLT. Originally, tissue-type plasminogen activator (t-PA) was considered to be responsible for the increases, but the efficacy of aprotinin which inhibits besides plasmin also kallikrein and urokinase-type plasminogen activator (u-PA) suggested also a role for the intrinsic and contact system-dependent plasminogen activators. We investigated the role of u-PA. From 29 patients undergoing OLT with intraoperative aprotinin infusion arterial blood samples were taken at 7 different time points. The preoperative median values for u-PA antigen (u-PA Ag) and plasmin-activatable single-chain u-PA (scu-PA) levels, which were more than 2-fold above normal (both: p < 0.01), decreased slightly during the preanhepatic phase and remained unchanged during the anhepatic phase. With reperfusion of the graft liver the two levels decreased significantly (p = 0.0003 and p = 0.006, respectively) to almost normal values, probably due to clearance by the graft liver. Active two-chain u-PA (tcu-PA) was preoperatively 2-fold above the detection limit, remained stable during the preanhepatic phase and increased 2-fold in the anhepatic phase (p = 0.0018). As expected tcu-PA also relapsed upon reperfusion, but to the preoperatively enhanced level, possibly caused by sustained activation of scu-PA by cathepsin B. t-PA activity levels were at the upper end of the normal range preoperatively, slightly increased during preanhepatic and anhepatic phases and decreased significantly with reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1996

Long-term treatment with growth hormone decreases plasminogen activator inhibitor-1 and tissue plasminogen activator in growth hormone-deficient adults.

The syndrome of growth hormone deficiency (GHD) in adults is associated with premature atherosclerosis, increased cardiovascular mortality, abnormal lipoprotein patterns and abnormal body composition. We have previously shown that GH-deficient adults have increased concentrations of fibrinogen and plasminogen activator inhibitor (PAI-1) activity. The aim of the present investigation was to study coagulation and fibrinolysis in 17 patients with adult-onset GHD during two years of treatment with recombinant human GH (12 micrograms/kg body weight/day). The impact of the contemporary changes in metabolic variables and body composition on coagulation and fibrinolysis was studied. The patients received conventional thyroid, adrenal and gonadal hormone replacement therapy. PAI-1 activity, PAI-1 antigen and tissue plasminogen activator (t-PA) antigen levels decreased during the GH treatment period (p < 0.05). The decrease was more pronounced in patients with high pre-treatment levels of the different variables. alpha 2-antiplasmin decreased (p < 0.05), while plasminogen was unchanged during two years of GH treatment. Fibrinogen concentrations tended to decrease after two years of GH treatment (p = 0.06), while the coagulation factors VII and VIII were unchanged. von Willebrand factor demonstrated a transient decrease after 18 months of GH treatment. The coagulation inhibitor, protein C, decreased (p < 0.05), while antithrombin was unchanged. Fasting plasma insulin increased (p < 0.01), but blood glucose did not differ after two years of GH treatment. Serum high-density lipoprotein cholesterol, total cholesterol and triglycerides were unaltered. Body fat decreased during the initial GH treatment but was unaltered after two years, while lean body mass increased (p < 0.001) and the waist over hip circumference ratio tended to decrease (p = 0.06). In conclusion, PAI-1 activity, PAI-1 antigen and t-PA antigen decreased during long-term GH treatment. These changes may be a direct effect of GH itself or may be secondary to the favourable changes in body composition. It remains to be seen whether changes in these fibrinolytic variables during rhGH treatment reduces the cardiovascular risk in patients with GHD. The present results suggest that GH plays a role in the regulation of fibrinolysis.

Adult↗
PubMed1996

[Tissue plasminogen activator and plasminogen activator inhibitor in aqueous humor].

BACKGROUND: In the anterior segment of the eye, fibrin clots must be rapidly resorbed to prevent fibrosis. Tissue-type plasminogen activator (t-PA), a serine protease that catalyzes the conversion from plasminogen to plasmin, plays an important role in the fibrinolytic system and has therefore in recent years attracted attention in the field of ophthalmology. MATERIAL AND METHODS: The aqueous humor of patients undergoing cataract surgery was analyzed for the presence of components of the fibrinolytic cascade. The quantities of t-PA and plasminogen-activator inhibitor (PAI) were determined using enzyme-linked immunosorbent assays. We determined t-PA and PAI in the aqueous humor of 64 patients between 59 and 82 years of age. RESULTS: The t-PA levels ranged from 0.65 to 1.75 ng/ml and PAI activity from 3.24 to 5.1 AU/ml. Association between t-PA levels and PAI activity and accompanying diseases or metabolic disorders was noted. The highest concentration of t-PA and the lowest activity of PAI has been observed in aqueous humor of patients with senile cataract. The knowledge about the presence of t-PA in aqueous humor is significant for the recognition of pathological events following intraocular fibrin formation and may be an important basis for therapeutic use of t-PA.

Aged↗
PubMed1995

Prostaglandin E2 regulates production of plasminogen activator isoenzymes, urokinase receptor, and plasminogen activator inhibitor-1 in primary cultures of rat calvarial osteoblasts.

The bone resorbing agent, prostaglandin E2 (PGE2), was found to alter several components of the plasminogen activator (PA)/plasmin pathway in primary cultures of rat neonatal osteoblast-like cells. The mRNA and activities of both urokinase-type PA (uPA) and tissue-type PA (tPA) were enhanced by PGE2 treatment. The presence of mRNA for the uPA receptor (uPAR) has been demonstrated in these cells and steady-state levels shown to be greatly enhanced, the response being rapid and sustained for at least 24 hours. mRNA for plasminogen activator inhibitor 1 (PAI-1) was modulated in a biphasic manner, with inhibition of the constitutive level apparent at 4 hours of treatment and stimulation apparent at 12 hours and longer, while PAI-1 protein, measured by an ELISA assay for rat PAI-1, was diminished over this period. Neither PAI-2 mRNA nor mRNA for the broad spectrum protease inhibitor, protease nexin-1 (PN-1), was found to be modulated by PGE2. Therefore, PGE2 is likely to stimulate cell surface proteolytic activity, since uPA mRNA and cell-associated activity were elevated, as was mRNA for the cellular receptor for uPA. Although it was not possible to measure uPAR number and affinity it seems likely that elevated uPAR mRNA would translate into increased uPARs which would localize the increased uPA activity to the pericellular region. tPA mRNA and activity were also increased transiently with the activity inhibited with prolonged incubations, apparently by PAI-1. Elevation of tPA mRNA and activity may result in elevated activity within the extracellular matrix as tPA has been reported to associate with several matrix proteins. Thus the early effect of PGE2 would be to promote proteolysis, both pericellularly and in the extracellular matrix. The inhibition of PAI-1 mRNA and protein, which would contribute to the elevation of activity, is due to PGE2, but the later stimulatory effect on PAI-1 mRNA may be due to feedback regulation by transforming growth factor beta (TGF beta), secreted by osteoblasts and activated by elevated levels of PA.

Amyloid beta-Protein Precursor↗
PubMed1994

Plasminogen activators and plasminogen activator inhibitors in blood and tumour fluids of patients with ovarian cancer.

We quantitated urokinase and tissue plasminogen activator (u-PA, t-PA), plasminogen activator inhibitor 1 and 2 (PAI-1, PAI-2), and fibrinolytic activity in peripheral blood (PB), tumour blood (TB), peritoneal/ascitic fluid (PAF) and cystic fluid (CF) from 104 patients with benign and 36 patients with malignant ovarian tumours, and in peripheral blood from 62 healthy controls. PB levels of u-PA were higher in patients with benign and malignant tumours than in controls. High concentrations of u-PA were found in CF, but not in TB, suggesting that u-PA is released by the tumour tissue, but not by the tumour vasculature. PB levels of t-PA were higher in both tumour groups than in controls. Increased levels of t-PA were found in TB, but not in CF, indicating that t-PA is released by the tumour vasculature, but not by the tumour tissue. PB levels of PAI-1 were higher in patients with both benign and malignant tumours than in controls. High levels of PAI-1 were present in both TB and CF from malignant tumours, suggesting that PAI-1 is released from the tumour vasculature as well as the tumour tissue. Elevated concentrations of PAI-2 were found in CF, but not in TB, indicating release from the tumour tissue, but not from the vasculature. High levels of t-PA, PAI-1 and PAI-2 were found in PAF of malignant tumours, and resorption from this compartment may explain elevated PB levels in patients with ascites. None of the PAs/PAIs proved useful as a PB marker for detection of early stage ovarian cancer. However, an index based on PAF levels of t-PA and PAI-1 discriminated between malignant and benign ovarian cysts in the absence of ascites. In addition, our study stresses the importance of including patients with benign tumours as well as healthy controls when markers for malignant tumours are evaluated.

Ascitic Fluid↗
PubMed1998

Activation of the urokinase plasminogen activator/urokinase plasminogen activator receptor system and redistribution of E-cadherin are associated with hepatocyte growth factor-induced motility of pancreas tumor cells overexpressing Met.

Because hepatocyte growth factor (HGF) is a potent mitogen for normal human exocrine pancreas cells (NPCs) in vitro, we have analyzed the expression of HGF and its receptor, Met, in NPC and pancreas cancer cells and studied its effects in vitro. Using immunohistochemistry, Northern blotting, and reverse transcription-polymerase chain reaction, we examined the expression of HGF and Met in normal pancreas and pancreas cancer. Scatter assays, wound-healing assays, and migration through transwell filters were used to study HGF-stimulated motility of IMIM-PC-2 cancer cells. In tumors, HGF is mainly detected in stromal cells, whereas Met is overexpressed in cancer cells with an unpolarized distribution. In vitro, HGF stimulates motogenesis but not proliferation in cancer cells. Cell motility is accompanied by a rapid decrease in the cytoskeleton-bound E-cadherin, an acceleration of cellular adhesion to the substrate, an up-regulation of urokinase plasminogen activator (u-PA) RNA and protein, and a change in the solubility and proteolysis of the u-PA receptor. Cell motility is significantly reduced by inhibitors of u-PA proteolytic activity such as antibodies neutralizing u-PA activity, plasminogen activator inhibitor 1, and amiloride. These results show that a paracrine loop of HGF activation may participate in the development or progression of pancreas cancer. In vitro, the HGF-stimulated motogenesis of pancreas cancer cells involves the activation of the u-PA/u-PA receptor proteolytic system, suggesting its role in the invasive stages of tumor progression.

Antibodies↗
PubMed1995

Biological mechanisms underlying the clinical effects of RU 486: modulation of cultured endometrial stromal cell plasminogen activator and plasminogen activator inhibitor expression.

The abortifacient and menstrual effects of the potent antiprogestin, RU 486, are associated with both endometrial hemorrhage and extracellular matrix (ECM) degradation. Such processes reflect reduced perivascular decidual cell hemostatic and increased ECM-degrading protease activity. Therefore, we assessed the effects of RU 486 administration on the expression of immunoreactive (ir) endometrial stromal cell urokinase-type (uPA) and tissue-type (tPA) plasminogen activator and their activities as well as levels of ir type 1 plasminogen activator inhibitor (PAI-1) using a well characterized in vitro model of decidualization. Thus, confluent stromal cell cultures were exposed to vehicle control, 10(-8) mol/L estradiol (E2), 10(-7)-10(-8) mol/L medroxyprogesterone acetate (MPA), E2 plus MPA, or 10(-6)-10(-7) mol/L RU 486 alone or in combination with MPA or E2 plus MPA for 3-4 days. Compared to the vehicle control, E2 and RU 486 used alone had no effect on levels of ir PAI-1, uPA, or tPA or on PA activity in the conditioned medium. In contrast, MPA and E2 plus MPA decreased ir uPA and tPA levels and their corresponding activities, whereas MPA increased, and E2 plus MPA further increased ir PAI-1 release. These effects of progestin were blocked by a log higher concentration of RU 486. Similar results were obtained for steady state PAI-1 messenger ribonucleic acid levels. To determine if RU 486 reversed progestin-inhibited stromal cell uPA and tPA release and progestin-enhanced PAI-1 expression, confluent cultures were exposed to 10(-8) mol/L E2 plus 10(-7) mol/L MPA for 10 days, washed, and reexposed to E2 plus MPA, steroid-free medium, or RU 486 for 3-5 or 9-11 days. Compared with cultures maintained in E2 plus MPA for 3-5 days, withdrawal to a steroid-free medium failed to affect stromal cell ir PAI-1, uPA, or tPA levels. In contrast, exposure to RU 486 for 3-5 days increased ir uPA and tPA levels 5- to 8-fold (P < 0.02) while reducing PAI-1 levels by 85% (P < 0.04). By 9-11 days of treatment, steroid withdrawal and RU 486 exerted similar effects on ir PAI-1, tPA, and uPA levels. Comparable results were obtained for PAI-1, uPA, and tPA steady state messenger ribonucleic acid levels. These findings indicate that RU 486 blocks and reverses progestin-inhibited PA expression, suggesting a mechanism for RU 486-induced endometrial hemorrhage and ECM dissolution.

Cells, Cultured↗
PubMed1984

Differences of frequency distributions of plasminogen phenotypes between Japanese and American populations: new methods for the detection of plasminogen variants.

Frequency distributions of various plasminogen phenotypes in Japanese and American white populations were studied using electrofocusing in polyacrylamide gels followed by zymography and immunofixation. Using a synthetic substrate, tosyl-lysine-alpha-naphthyl ester, for zymography allowed zymography and immunofixation to be performed sequentially on the same gel plate. By this method, a nonfunctional abnormal plasminogen variant, plasminogen Tochigi, was readily detected in both plasma and serum. The gene frequency of this abnormal variant in a Japanese population was 0.018, whereas the abnormal variant was not detected in an American white population, suggesting the very rare occurrence of this variant in whites. Two common alleles, A and B, clearly identified in neuraminidase-treated samples, were observed at gene frequencies of 0.98 and 0.003, respectively, in the Japanese. These values are significantly different from the reported values in whites of 0.69 for A and 0.3 for B.

Gene Frequency↗
PubMed1986

A spectrophotometric solid-phase fibrin-tissue plasminogen activator activity assay (SOFIA-tPA) for high-fibrin-affinity tissue plasminogen activators.

A new spectrophotometric solid-phase fibrin-tissue plasminogen activator activity assay (SOFIA-tPA), specific for the quantitation of tissue plasminogen activators, is described. The method is based on (1) the high-affinity binding (Kp = 1.4 +/- 2 nM) of tPA to a solid-phase fibrin network constructed by thrombin proteolysis of fibrinogen covalently coupled to polyglutaraldehyde-activated polyvinyl chloride microtiter plates, and (2) the subsequent development of PA activity by the fibrin-tPA complex and its measurement with a coupled assay using a chromogenic substrate highly selective for plasmin. Conditions were chosen such that the rate of para-nitroaniline release from the substrate is directly proportional to the concentration of tPA. The support is able to isolate tPA from the bulk of proteins present in any biological fluid allowing the assay to specifically detect tPA activity (range: 0.01 to 50 IU/ml) even in the presence of other activators, proteases, and inhibitors. Since the assay is done in a well-defined reaction mixture (the fibrin-tPA complex, plasminogen, and the synthetic substrate), kinetics studies using pure or crude tPA can be performed. Standard curves (rate measurement and endpoint methods) were made using the international standard (preparation 83/517) for tPA.

Animals↗
PubMed1989

Comparison of recombinant tissue-type plasminogen activator (rt-PA) expressed in mouse C127 cells and human vascular plasminogen activator (HV-PA).

Tissue-type plasminogen activator produced by recombinant DNA technology (rt-PA) has now been recognized as a promising clot-selective thrombolytic agent. We have compared the properties of rt-PA expressed in mouse C127 cells with those of naturally occurring human vascular plasminogen activator (HV-PA). The molecular weight of HV-PA and rt-PA was estimated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to be approx. 66,000. HV-PA and rt-PA were labile and rapidly lost their activities at pH values below 5.5. The optimum pH of HV-PA and rt-PA for plasminogen activation was around 8.5. HV-PA and rt-PA appeared to be very similar in amidolytic properties, amino-acid composition and carbohydrate composition. Moreover, the N-terminal amino-acid sequence of HV-PA was in good agreement with that of rt-PA. The purified preparations of HV-PA and rt-PA had specific activities of about 250,000 and 600,000 IU/mg, respectively. Both activators bound to fibrin clots to similar degree. In immunodiffusion as well as in the quenching experiments of the fibrinolytic activities, rt-PA appeared to be immunodiffusion as well as in the quenching experiments of the fibrinolytic activities, rt-PA appeared to be immunologically indistinguishable from HV-PA. All these findings indicate that rt-PA expressed in mouse C127 cells is identical with naturally occurring HV-PA in physical and chemical properties.

Amino Acid Sequence↗
PubMed1988

Human tissue-type plasminogen activator synthesized by using a baculovirus vector in insect cells compared with human plasminogen activator produced in mouse cells.

A cDNA fragment encoding the human tissue-type plasminogen activator was inserted into the baculovirus Autographa californica nuclear polyhedrosis virus downstream from the polyhedrin promoter. The induction kinetics of t-PA was followed, after infection of Spodoptera frugiperda cells, at both mRNA and protein levels. Fibrinolytically active plasminogen activator accumulated in the culture medium and reached 2.5 micrograms/ml after 120 h. The protein was compared with recombinant plasminogen activator produced in mouse cells and was found to be slightly smaller. This difference in size was found to be caused by N-linked oligosaccharides which are shorter in the recombinant activator obtained from insect cells. The molecules produced in such cells contain at least two different types of N-linked glycans, since only one out of three oligosaccharides is sensitive to endoglycosidase H. However, all glycan structures bind strongly to concanavalin A-Sepharose.

Animals↗
PubMed1995

Plasminogen kringle 4 binds the heptapeptide fragment 44-50 of the plasminogen N-terminal peptide.

The interaction between the plasminogen kringle 4 module and a synthetic peptide corresponding to the tryptic heptapeptide fragment Ala-Phe-Gln-Tyr-His-Ser-Lys (AFQYHSK), segment 44-50 of the plasminogen N-terminal peptide (Wiman and Wallén, Eur J Biochem 1975; 50:489-494), has been investigated by 1H-NMR spectroscopy. AFQYHSK, as well as the shorter fragments thereof, FQYHSK, QYHSK and YHSK, all bound to kringle 4 with equilibrium association constant (Ka) values ranging between 2.5 and 8.5 mM-1. The NMR evidence also indicates that binding is mediated by the canonical kringle lysine binding site and involves the C-terminal Lys residue of the ligand peptide. The results (a) support a potential interaction between plasminogen Lys-binding kringles and the N-terminal activation peptide, and (b) unambiguously demonstrate the capability of such kringles to bind polypeptides ending with C-terminal lysine.

Amino Acid Sequence↗
PubMed1987

Activation with plasmin of tow-chain urokinase-type plasminogen activator derived from single-chain urokinase-type plasminogen activator by treatment with thrombin.

Thrombin converts single-chain urokinase-type plasminogen activator (scu-PA) to an inactive two-chain derivative (thrombin-derived tcu-PA) by hydrolysis of the Arg-156--Phe-157 peptide bond. In the present study, we show that inactive thrombin-derived tcu-PA (specific activity 1000 IU/mg) can be converted with plasmin to active two-chain urokinase-type plasminogen activator (specific activity 43,000 IU/mg) by hydrolysis of the Lys-158--Ile-159 peptide bond. This conversion follows Michaelis-Menten kinetics with a Michaelis constant Km of 37 microM and a catalytic rate constant k2 of 0.013 s-1. The catalytic efficiency (k2/Km) for the activation of thrombin-derived tcu-PA by plasmin is about 500-fold lower than that for the conversion of intact scu-PA to tcu-PA. tcu-PA, generated by plasmin treatment of thrombin-derived tcu-PA, has similar properties to tcu-PA obtained by digestion of intact scu-PA with plasmin (plasmin-derived tcu-PA); its plasminogen activating potential and fibrinolytic activity in an in vitro plasma clot lysis system appear to be unaltered. These observations confirm that the structure of the NH2-terminal region of the B chain of u-PA is an important determinant for its enzymatic activity, whereas that of the COOH-terminal region of the A chain is not.

Amino Acids↗
PubMed1993

Thrombolytic effect of a plasminogen-plasminogen activator chimera in a photochemically induced thrombosis (PIT) model.

The thrombolytic effects of the plasminogen/plasminogen activator chimera (SUN9216), comprising the fibrin-binding kringle 1 domain of plasminogen and two kringle and the serine protease domain of the wild-type tissue plasminogen activator (t-PA) including a modification of the mannose glycosylation on the kringle 1 of t-PA (PK1 delta FE1X), was compared with tht of t-PA by use of a photochemically induced thrombus (PIT) in the rat femoral artery. When SUN9216 was administered either as an i.v. infusion (1.0 mg kg-1) or as a single bolus i.v. injection (1.0 mg kg-1), all parameters were markedly improved compared to t-PA administered as an i.v. infusion (3.0 mg kg-1). A higher concentration of plasminogen activator (PA) activity in plasma was observed after administration of SUN9216 which persisted for longer than that after t-PA. It is concluded that the thrombolytic effect of SUN9216 is markedly greater than that of t-PA.

Animals↗
PubMed1968

Effect of urokinase antiserum on plasminogen activators: demonstration of immunologic dissimilarity between plasma plasminogen activator and urokinase.

Antiserum against purified human urokinase was produced by immunization of Hartley strain guinea pigs. The antiserum was capable of neutralizing the plasminogen activator activity of the antigen and of native urokinase in human urine. The antiserum did not inhibit plasminogen activators of bacterial origin, i.e., streptokinase and staphylokinase; neither did it inhibit urokinase from nonprimate mammals, i.e., dog, pig, rabbit, guinea pig, nor tissue activator or tissue culture supernatants from porcine sources. Partial cross-reactivity against urokinase from primates, i.e., rhesus monkey and baboon, was noted as well as with supernatant from rhesus kidney tissue culture. In vitro studies showed lack of immunologic identity between human urokinase and human milk activator or human tissue activator from adrenal sources but demonstrated immunologic identity between human urokinase and the supernatant from human kidney tissue culture. In vivo studies in man failed to show detectable levels of urokinase activity in peripheral venous or renal venous blood under a variety of clinical states and when stimuli such as exercise, electroshock therapy, or nicotinic acid were used to enhance plasminogen activator activity in the plasma. The results establish that human plasma activator, milk activator, and tissue activator from the adrenals are immunologically distinct from human urokinase.

Acetylesterase↗
PubMed2006

Interplay of human tissue kallikrein 4 (hK4) with the plasminogen activation system: hK4 regulates the structure and functions of the urokinase-type plasminogen activator receptor (uPAR).

The plasminogen activation system is involved in cancer progression and metastasis. Among other proteolytic factors, it includes the serine protease urokinase-type plasminogen activator (uPA) and its three-domain (D1D2D3) receptor uPAR (CD87), which focuses plasminogen activation to the cell surface. The function of uPAR is regulated in part through shedding of domain D1 by proteases, e.g., uPA itself or plasmin. Human tissue kallikrein 4 (hK4), which is highly expressed in prostate and ovarian tumor tissue, was previously shown to cleave and activate the pro-enzyme forms of prostate-specific antigen (PSA, tissue kallikrein hK3) and uPA. Here we demonstrate that uPAR is also a target for hK4, being cleaved in the D1-D2 linker sequence and, to a lesser extent, in its D3 juxtamembrane domain. hK4 may thus modulate the tumor-associated uPA/uPAR-system activity by either activating the pro-enzyme form of uPA or cleaving the cell surface-associated uPA receptor.

Dose-Response Relationship, Drug↗
PubMed1993

Thrombolytic and haemorrhagic effects of bolus doses of tissue-type plasminogen activator and a hybrid plasminogen activator with prolonged plasma half-life (K2tu-PA: CGP 42935).

K2tu-PA is a hybrid plasminogen activator linking the kringle 2 domain of tissue-type plasminogen activator (t-PA) to the catalytic protease domain of single-chain urokinase-type plasminogen activator (scu-PA). K2tu-PA, as t-PA has high affinity for fibrin and is activated by fibrin but has a longer plasma half-life (over 30 min). The aim of this study was to compare the effects of bolus doses of recombinant t-PA (rt-PA) and K2tu-PA, on: 1) lysis of performed thrombi (fibrinolysis), 2) accretion of new fibrin on pre-existing thrombi during fibrinolysis (thrombus growth), 3) thrombolysis as assessed by reduction of thrombus weight and 4) systemic plasma proteolysis and blood loss from a standard wound. A jugular vein thrombosis model and an ear bleeding model were adopted in rabbits. Saline produced 11 +/- 2% fibrinolysis. rt-PA, 0.2 mg/kg, 0.4 mg and 0.8 mg/kg produced 35 +/- 4%, 54 +/- 4% and 78 +/- 6% fibrinolysis, respectively. K2tu-PA, at the same doses, produced 39 +/- 5%, 57 +/- 6% and 83 +/- 6% fibrinolysis, respectively. Thus, no differences in the fibrinolytic activity of rt-PA and K2tu-PA were observed. Injection of saline was followed by an accretion of 56.4 +/- 5.9 micrograms of radioactive new fibrin on the thrombi. The injection of the three increasing doses of rt-PA was followed by an accretion of 54.9 +/- 5.3 micrograms, 49.1 +/- 6.1 micrograms and 47.2 +/- 4.8 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗