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PubMed1990

6-aminohexanoate and chloride ion in the activation by urokinase of porcine plasminogens.

The rate of activation by urokinase of porcine plasminogen is accelerated by 6-aminohexanoate, although the maximally enhanced rate is 10-fold less than that of human plasminogen without the amino acid. 6-Aminohexanoate facilitates only activation of native porcine plasminogen (asp-plasminogen), but has no effect on activation of des-kringle1-4-plasminogen. Sodium chloride, on the other hand, inhibits activation by urokinase of both porcine asp-plasminogen and des-kringle1-4-plasminogen. It is concluded that 6-aminohexanoate exerts its effect via kringle1-4 domains of plasminogen, whereas Cl- acts, at least in part, through effects on the kringle5 or proteinase domains.

Aminocaproates↗
PubMed1977

Plasminogen activator from human embryonic kidney cell cultures. Evidence for a proactivator.

The nature of the trypsin-activatable plasminogen activator produced by kidney cell cultures (Bernik, M.B (1973), J. Clin. Invest. 52, 823-834) was investigated using human embryonic kidney (HEK) cell cultures in serum-free medium. Plaminogen activator activity ratios (trypsin-activated/ untreated controls) in HEK cell-conditioned media were maximal (up to 3) during the first week of culture and remained nearly constant at approximatley 2 for the next 3-5 weeks, while the total plasminogen activator titer increased in a nearly linear manner. Therefore, coincident with progressive cell degeneration and death, the ratios decreased to near unity due to "spontaneous" activation of the enzyme, which was inhibited in cell-free conditioned media by the pancreatic trypsin inhibitor Kunitz and benzamidine. Since the activator is not inhibited by the trypsin inhibitor, it is concluded that a protease other than the plasminogen activator is responsible for the activation. Increases in the plasminogen activator titers (about 2-fold) were similarly obtained by culturing the cells in medium containing low concentrations (0.05-0.10 mug/ml) of trypsin for up to about 6 weeks. The presence of the trypsin inhibitor in HEK cells cultures decreased the rate of activation, resulting in higher activity ratios (up to 6), and the total plasminogen activator activity was reduced only minimally (less than 20%), if at all, by the highest concentration of the trypsin inhibitor (100 mug/ml) tested. Affinity chromatography of conditioned media with activity ratios of 1.6--2 separated the plasminogen activator into an active fraction and a fraction which was activated a minimum of 200-fold by trypsin and contained no measurable activity prior to activation. Gel filtration of crude conditioned media or partially purified activator separated the plasminogen activator into two peaks; both were trypsin-activatable, and their relative proportions varied with the isolated conditions. The results indicate the occurrence of a proenzyme form of the plasminogen activator in the culture media.

Antibodies↗
PubMed1978

Characterization of plasminogen activator in human cervical cells.

Plasminogen activator activity was detected in human gynecologic specimens using a synthetic fluorogenic peptide substrate assay and confirmed by an 125I-labeled fibrin plate assay. Epithelial cells in these samples contain enzymatic activity that biochemically resembles both the well-characterized plasminogen activator, urokinase, and the less-specific plasminogen activator, trypsin. Inhibition of the cervical cell activity by diisopropylfluorophosphate and p-nitrophenyl-p'-guanidinobenzoate demonstrates that, like urokinase and trypsin, this plasminogen activator is also a serine protease. Polyacrylamide gel electrophoresis of plasminogen that had been incubated with cervical cells indicated the same mechanism of plasminogen activation as exhibited by urokinase. We attempted to correlate plasminogen activator activity of each sample with cytomorphologic diagnosis. Three of the four dysplastic samples analyzed showed higher plasminogen activator activity than did the normal samples.

Cervix Uteri↗
PubMed1987

Interleukin 1 preferentially stimulates the production of tissue-type plasminogen activator by human articular chondrocytes.

Interleukin 1, derived from human placenta, stimulates plasminogen activator activity in human articular chondrocytes. The stimulation of plasminogen activator activity can be abolished by preincubation of placental interleukin 1 with an antiserum to homogeneous 22K factor, a species of interleukin 1 beta, indicating that the stimulation of plasminogen activator activity is due to interleukin 1 and not contaminating factors. Chondrocytes produce three species of plasminogen activator, with apparent Mr approximately 50,000, 65,000 and 100,000 as determined after sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis with gels containing casein and plasminogen. Both placental interleukin 1 and 22K factor enhance the production of the species of Mr approximately 65,000 and 100,000. Comparison of the mobility of the plasminogen activator species on SDS-polyacrylamide gel electrophoresis with human urokinase (u-PA) and human melanoma tissue-type plasminogen activator (t-PA) and studies with antibodies to these enzymes indicate that the Mr approximately 50,000 species is a u-PA and the Mr approximately 65,000 a t-PA. The Mr approximately 100,000 species is possibly an enzyme-inhibitor complex. Interleukin 1 therefore appears to enhance the production of t-PA and a putative enzyme-inhibitor complex. Abolition of plasminogen activator activity in the fibrin plate assay with antibodies to t-PA and u-PA also confirms enhanced t-PA production on interleukin 1 stimulation, though there is also evidence for increased cell-associated production of u-PA.

Cartilage, Articular↗
PubMed1998

Induction of plasminogen in rat hippocampal pyramidal neurons by kainic acid.

Tissue plasminogen activator (tPA) is used to treat acute stroke, but tPA- and plasminogen-gene-deficient mice exhibit resistance to neurodegeneration. Thus, it is unclear whether the tPA-plasminogen system, an extracellular proteolytic cascade plays a helpful or harmful role, and whether plasminogen is induced by neurodegeneration. In the CA3, kainic acid (KA)-injection caused neuronal damage after 6 h, and almost all of the neurons were lost after 7 days. Plasminogen mRNA was strongly induced 6 h after injection, then gradually decreased, and was very weak at 2 days after injection. Plasminogen protein was expressed after 6 h and localized in abnormally shaped neurons. The in vivo expression of plasminogen was synchronous with morphological changes in neurons. These results suggest that the expression of plasminogen induced by KA-injection may disrupt of neuron-extracellular matrix interaction and thereby contribute to cell death in neurons in the hippocampus.

Animals↗
PubMed1994

Substitution of arginine 719 for glutamic acid in human plasminogen substantially reduces its affinity for streptokinase.

In isolation human plasminogen possesses no enzymatic activity, yet upon formation of an equimolar complex with the bacterial protein streptokinase, it acquires a plasminogen activator function. The region(s) of plasminogen and of streptokinase which mediate complex formation has (have) not been previously published. Here it is reported that a single-residue substitution (Arg719-->Glu) in the serine protease domain of full-length Glu-plasminogen substantially reduces its affinity for streptokinase. The plasminogen variant displays no other significant differences from the wild-type molecule with respect to activation by two-chain urokinase-type plasminogen activator, recognition by monoclonal antibodies, or ability to undergo conformational change. It is concluded that Arg719 in human plasminogen is an important determinant of the streptokinase binding site, although further sites are likely to contribute both to the affinity of plasminogen for streptokinase and to mechanisms by which the active site is formed within the complex.

Animals↗
PubMed1984

Increased activity of plasminogen activators during involution of the rat ventral prostate.

Plasminogen activator was measured in the ventral prostates of non-castrated, castrated, and androgen-treated rats to determine whether changes in this activity correlated with the process of glandular involution. While the activity was very low in cytosolic extracts from the prostates of non-castrated rats, 2 days following castration the plasminogen activator activity increased in a near-linear fashion such that by day 7 it was 10-fold higher in terms of specific activity (per mg of protein) and cellular concentration (per mg of DNA). During this interval there was a rapid decrease in the cell population of the prostates. Treatment of the 7-day castrated rats with the potent androgen, dihydrotestosterone, both reduced the plasminogen activator activity and restored the cell number in a dose-related manner. Gel electrophoretic analysis revealed two major bands of plasminogen activator activity in the cytosolic extracts from 4- and 7-day castrated rats, plus additional minor bands in samples from 10- and 14-day castrated rats. Approx. 10% of the cellular concentration of plasminogen activator activity was recovered in association with an 18000g pellet fraction from the prostates; this fraction showed less heterogeneity of the plasminogen activator forms as observed by gel electrophoresis. Inhibitor studies indicated that the 18000g pellet fraction from the prostates of non-castrated rats possessed some plasminogen activator inhibitor activity, but the relative concentration of the inhibitor activity was small. We conclude that the involution of the prostate is probably associated with increased synthesis of plasminogen activators through a de-repression process which may involve loss of androgen receptors.

Animals↗
PubMed2001

Cancer cell expression of urokinase-type plasminogen activator receptor mRNA in squamous cell carcinomas of the skin.

In this study we have used in situ hybridization with radiolabeled antisense RNA probes to examine the expression of mRNA for urokinase-type plasminogen activator and its receptor in histologic samples of squamous cell (n = 7) and basal cell (n = 7) carcinomas of the skin. Messenger RNA for both urokinase-type plasminogen activator and its receptor were expressed in all of the squamous cell carcinomas, but could not be detected in the basal cell carcinomas. In all of the seven squamous cell carcinomas a signal for urokinase-type plasminogen activator receptor mRNA was detected focally in well-differentiated cancer cells surrounding keratinized pearls, and in four specimens urokinase-type plasminogen activator receptor mRNA was in addition expressed by cancer cells at the edge of invasively growing strands of tumor. Urokinase-type plasminogen activator mRNA expression was found in virtually all the cancer cells of the squamous cell carcinomas, and importantly we found, by hybridizations for urokinase-type plasminogen activator and its receptor mRNA on adjacent sections of squamous cell carcinomas, that it was exactly the invading cancer cells that simultaneously expressed both these components required for plasmin-mediated proteolysis at the cell surface. We have previously shown that both urokinase-type plasminogen activator and its receptor mRNA are expressed by the leading-edge keratinocytes in regenerating epidermis during mouse skin wound healing, and that wound healing is impaired in mice made deficient in plasminogen by targeted gene disruption. We propose that there are similarities between the mechanisms of generation and regulation of extracellular proteolysis during skin re-epithelialization and squamous cell carcinoma invasion. The ability of the squamous carcinoma cells to mimic the "invasive" phenotype of re-epithelializing keratinocytes may be one of the factors that make squamous cell carcinomas more aggressive tumors than basal cell carcinomas.

Basal Cell Carcinoma↗
PubMed1981

Rapid purification of a high-affinity plasminogen activator from human blood plasma by specific adsorption on fibrin/Celite.

A preparation of fibrin precipitated over a solid Celite (diatomaceous earth) matrix that selectively binds 50-70% of the plasminogen activator present in human blood plasma is described. Affinity chromatography of plasma on fibrin/Celite followed by gel filtration led to a 29,000-fold purification of the plasminogen activator. The activator, referred to as the high-affinity plasminogen activator, is characterized by its ability to be strongly adsorbed by fibrin. Smaller amounts of other plasminogen activators and essentially all plasminogen were not bound to fibrin. The high-affinity plasminogen activator is a single-chain unstable protease with a molecular weight of 65,000-70,000. The high-affinity plasminogen activator has a low specific activity (500 CTA units/mg) compared to tissue or urine plasminogen activators (100,000-200,000 CTA units/mg) (CTA, Committee on Thrombolytic Agents).

Chromatography, Affinity↗
PubMed1995

Enhancement of the enzymatic activity of single-chain urokinase plasminogen activator by soluble urokinase receptor.

Single-chain urokinase (scuPA), the unique form of urokinase secreted by cells, is converted to an active two-chain molecule through the cleavage of a single peptide bond by plasmin and other specific proteinases. Although scuPA may express limited enzymatic activity, its contribution to plasminogen activation on cell surfaces remains uncertain. Further, although it is well known that scuPA binds to a specific extracellular urokinase-type plasminogen activator receptor, the effect of this interaction on the enzymatic activity of scuPA has not been described. In the present paper we report that the binding of scuPA to cellular an to recombinant soluble urokinase-type plasminogen activator receptors (suPAR) increases its catalytic activity as measured by the cleavage of a urokinase-specific chromogenic substrate. suPAR increased the Vmax of scuPA 5-fold with little change in its Km. suPAR also stimulated the plasminogen activator activity of scuPA by decreasing its Km for Glu-plasminogen from 1.15 microM to 0.022 microM and by increasing the kcat of this reaction from 0.0015 to 0.022 s-1. Preincubation of scuPA with suPAR also enhances its susceptibility to inhibition by plasminogen activator inhibitor type 1, consistent with exposure of its catalytic site. The activity of scuPA bound to suPAR is not accompanied by cleavage of scuPA, which continues to migrate as a single band in SDS-polyacrylamide gel electrophoresis under reducing conditions. Moreover, suPAR increases the plasminogen activator activity of a plasmin-insensitive variant, scuPA (scuPA-Glu158), as well. Enhancement of scuPA activity by suPAR is both prevented and reversed by its aminoterminal fragment (amino acids 1-135), which competes for receptor binding, suggesting that continued binding to the receptor is required for expression of scuPA's enzymatic activity. Thus, our data suggest that scuPA may undergo a reversible transformation between a latent and an active state. The urokinase receptor may induce or stabilize scuPA in its active conformation, thereby contributing to the initiation of plasminogen activation on cell surfaces.

Peptide Fragments↗
PubMed2001

Purification, cloning, and characterization of a profibrinolytic plasminogen-binding protein, TIP49a.

The plasminogen receptors responsible for enhancing cell surface-dependent plasminogen activation expose COOH-terminal lysines on the cell surface and are sensitive to proteolysis by carboxypeptidase B (CpB). We treated U937 cells with CpB, then subjected membrane fractions to two-dimensional gel electrophoresis followed by ligand blotting with (125)I-plasminogen. A 54-kDa protein lost the ability to bind (125)I-plasminogen after treatment of intact cells and was purified by two-dimensional gel electrophoresis and then sequenced by mass spectrometry. Two separate amino acid sequences were obtained and were identical to sequences contained within human and rat TIP49a. The cDNA for the 54-kDa protein matched the human TIP49a sequence, and encoded a COOH-terminal lysine, consistent with susceptibility to CpB. Antibodies against rat TIP49a recognized the plasminogen-binding protein on two-dimensional Western blots of U937 cell membranes. Human (125)I-Glu-plasminogen bound specifically to TIP49a protein, and binding was inhibited by epsilon-aminocaproic acid. A single class of binding sites was detected, and a K(d) of 0.57 +/- 0.14 microm was determined. TIP49a enhanced plasminogen activation 8-fold compared with the BSA control, and this was equivalent to the enhancement mediated by plasmin-treated fibrinogen. These results suggest that TIP49a is a previously unrecognized plasminogen-binding protein on the U937 cell surface.

ATPases Associated with Diverse Cellular Activitie↗
PubMed2004

Conservation of critical functional domains in murine plasminogen activator inhibitor-1.

Plasminogen activator inhibitor-1 is the main physiological regulator of tissue-type plasminogen activator in normal plasma. In addition to its critical function in fibrinolysis, plasminogen activator inhibitor-1 has been implicated in roles in other physiological and pathophysiological processes. To investigate structure-function aspects of mouse plasminogen activator inhibitor-1, the recombinant protein was expressed in Escherichia coli and purified. Five variant recombinant murine proteins (R76E, Q123K, R346A, R101A, and Q123K/R101A) were also generated using site-directed mutagenesis. The variant (R346A) was found to be defective in its inhibitory activity against tissue plasminogen activator relative to its wild-type counterpart. Enzyme-linked immunosorbent assay and surface plasmon resonance experiments demonstrated reduced vitronectin-binding affinity of the (Q123K) variant (K(D) = 1800 nm) relative to the wild-type protein (K(D) = 5.4 nm). Kinetic analyses indicated that the (Q123K) variant had a slower association (k(on) = 2.92 x 10(4) m(-1) s(-1)) to, and a faster dissociation from, vitronectin (k(off) = 5.3 x 10(-2) s(-1)), (wild-type k(on) = 1.03 x 10(6) m(-1) s(-1) and k(off) = 5.27 x 10(-3) s(-1)). The Q123K/R101A variant demonstrated an even lower vitronectin-binding ability. Low density lipoprotein receptor-related protein binding was decreased for the (R76E) variant. It was also demonstrated that the plasminogen activator inhibitor-1/vitronectin complex decreased the interaction of plasminogen activator inhibitor-1 with low density lipoprotein receptor-related protein. These results indicate that the complex interactions traditionally associated with different plasminogen activator inhibitor-1 functions apply to the murine system, thus showing a commonality of subtle functions among different species and evolutionary conservation of this protein. Further, this study provides additional evidence that the human hemostasis system can be studied effectively in the mouse, which is a great asset for investigations with gene-altered mice.

Animals↗
PubMed1996

Differential effects of tissue plasminogen activator and streptokinase on infarct size and on rate of enzyme release: influence of early infarct related artery patency. The GUSTO Enzyme Substudy.

BACKGROUND: The recent international GUSTO trial of 41,021 patients with acute myocardial infarction demonstrated improved 90-min infarct related artery patency as well as reduced mortality in patients treated with an accelerated regimen of tissue plasminogen activator, compared to patients treated with streptokinase. A regimen combining tissue plasminogen activator and streptokinase yielded intermediate results. The present study investigated the effects of treatment on infarct size and enzyme release kinetics in a subgroup of these patients. METHODS: A total of 553 patients from 15 hospitals were enrolled in the study. Four thrombolytic strategies were compared: streptokinase with subcutaneous heparin, streptokinase with intravenous (i.v.) heparin, tissue plasminogen activator with i.v. heparin, and streptokinase plus tissue plasminogen activator with i.v. heparin. The activity of alpha-hydroxybutyrate dehydrogenase (HBDH) in plasma was centrally analysed and infarct size was defined as cumulative HBDH release per litre of plasma within 72 h of the first symptoms (Q(72)). Patency of the infarct-related vessel was determined by angiography in 159 patients, 90 min after treatment. RESULTS: Infarct size was 3.72 g-eq.1(-1) in patients with adequate coronary perfusion (TIMI-3) at the 90 min angiogram and larger in patients with TIMI-2 (4.35 g-eq.1(-1) or TIMI 0-1 (5.07 g-eq.1(-1) flow (P = 0.024). In this subset of the GUSTO angiographic study, early coronary patency rates (TIMI 2 + 3) were similar in the two streptokinase groups (53 and 46%). Higher, but similar, patency rates were observed in the tissue plasminogen activator and combination therapy groups (87 and 90%). Median infarct size for the four treatment groups, expressed in gram-equivalents (g-eq) of myocardium, was 4.4, 4.5, 3.9 and 3.9 g-eq per litre of plasma (P = 0.04 for streptokinase vs tissue plasminogen activator). Six hours after the first symptoms, respectively 5.3, 6.6, 14.0 and 13.6% of total HBDH release was complete (P < 0.0001 for streptokinase vs tissue plasminogen activator). CONCLUSIONS: Rapid and complete coronary reperfusion salvages myocardial tissue, resulting in limitation of infarct size and accelerated release of proteins from the myocardium. Treatment with tissue plasminogen activator, resulting in earlier reperfusion was more effective in reducing infarct size than the streptokinase regimens, which contributes to the differences in survival between treatment groups in the GUSTO trial.

Humans↗
PubMed2006

Targeting urokinase-type plasminogen activator and its receptor for cancer therapy.

Cancer invasion and metastasis are highly complex processes and a serine protease urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system has been postulated to play a central role in the mediation of cancer progression. Of note, malignant tumor urokinase-type plasminogen activator and urokinase-type plasminogen activator receptor levels have been found to vary considerably, and to be related to patient prognosis. In mouse models, the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system has been studied extensively as a target for anticancer therapy using a variety of approaches. In this review, we discuss the advances in the various modalities that have been used to target the urokinase-type plasminogen activator/urokinase-type plasminogen activator receptor system, including protein-based and peptide-based drugs, antisense therapy, and RNA interference technology. In particular, preclinical mouse model studies that used human tumor xenografts are reviewed.

Animals↗
PubMed1992

Two types of receptors for human plasminogen on group G streptococci.

To investigate the nature of plasminogen binding to streptococci, strains selected for high reactivity with human plasminogen were examined for binding pattern against a panel of plasminogen fragments. The strains included human isolates of groups A, C and G as well as bovine isolates of group G. All strains reacted substantially with the plasminogen fragment kringle 1-3. Using the miniplasminogen fragment (kringle 5 and the B chain) a small but reproducible uptake was detected for human group G strains but not for group A or C strains. The group G strains of bovine origin on the other hand demonstrated high uptake of miniplasminogen, suggesting the possibility of an alternative plasminogen receptor for this species. This interpretation was supported by blocking experiments with the lysine analogue EACA where low concentrations (1 mM) completely blocked plasminogen binding to human streptococci, whereas a 100-fold higher concentration was needed for bovine group G strains. Scatchard plots with human isolates resulted in straight lines and Kd values were generally in the range of 20-80 nM. The number of receptors was estimated to be 45,000 for a selected group A strain and about 10,000 for the selected group C and G strains. Scatchard analysis with bovine group G isolates on the other hand revealed a two phase interaction, supporting the assumption of two different receptor structures on these strains. Kd for the first phase was estimated to be about 20 nM (10,000-20,000 receptors per bacterium), which was similar to the human strains, whereas the second phase was in the range of 400-500 nM (50,000 and 150,000 receptors per bacterium with two selected strains). Scatchard plots with the miniplasminogen fragment as ligand mimicked the phase two reaction with plasminogen, supporting the concept that this reaction represents a new and not previously described receptor. Both the receptor reacting with the kringle 1-3 portion and the one reacting with the miniplasminogen portion bound plasmin and plasminogen with similar affinity.

Aprotinin↗
PubMed1995

Borrelia burgdorferi binds plasminogen, resulting in enhanced penetration of endothelial monolayers.

Several strains of Borrelia burgdorferi and Borrelia hermsii can bind human Lys-plasminogen specifically. Affinity blots using 125I-labeled plasminogen showed that numerous polypeptides of all the strains and species tested could bind via lysine residues to the plasminogen molecule since binding could be completely inhibited by the lysine analog epsilon-aminocaproic acid. Binding analysis using 125I-labeled plasminogen on live intact organisms showed that the organisms possess two binding sites for plasminogen: a high-affinity site with a Kd of 24 +/- 12 pM and 106 +/- 14 binding sites per spirochete and a low-affinity site with a Kd of 20 +/- 4 nM and 2,683 +/- 36 binding sites per spirochete. Indirect immunofluorescence and confocal microscopy showed a generalized but punctate pattern of plasminogen binding to the spirochete surface. Exogenously provided urokinase-type plasminogen activator converted B. burgdorferi surface-bound plasminogen to enzymatically active plasmin as demonstrated by the breakdown of the chromogenic plasmin substrate S2251. Plasmin-coated organisms showed an enhanced ability to penetrate endothelial cell monolayers grown on connective tissue substrates compared to untreated controls (P < 0.001). This functional assay demonstrated that enzymatically active plasmin on the surface of spirochetes can lead to greater invasion of tissues.

Amnion↗
PubMed1987

Binding of tissue plasminogen activator to cultured human endothelial cells.

Tissue plasminogen activator (t-PA) and urokinase (u-PA), the major activators of plasminogen, are synthesized and released from endothelial cells. We previously demonstrated specific and functional binding of plasminogen to cultured human umbilical vein endothelial cells (HUVEC). In the present study we found that t-PA could bind to HUVEC. Binding of t-PA to HUVEC was specific, saturable, plasminogen-independent, and did not require lysine binding sites. The t-PA bound in a rapid and reversible manner, involving binding sites of both high (Kd, 28.7 +/- 10.8 pM; Bmax, 3,700 +/- 300) and low (Kd, 18.1 +/- 3.8 nM; Bmax 815,000 +/- 146,000) affinity. t-PA binding was 70% inhibited by a 100-fold molar excess of u-PA. When t-PA was bound to HUVEC, its apparent catalytic efficiency increased by three- or fourfold as measured by plasminogen activation. HUVEC-bound t-PA was active site-protected from its rapidly acting inhibitor: plasminogen activator inhibitor. These results demonstrate that t-PA specifically binds to HUVEC and that such binding preserves catalytic efficiency with respect to plasminogen activation. Therefore, endothelial cells can modulate hemostatic and thrombotic events at the cell surface by providing specific binding sites for activation of plasminogen.

Binding Sites↗
PubMed1995

Plasma carboxypeptidases as regulators of the plasminogen system.

Carboxy-terminal lysine residues on the surface of cells and fibrin bind plasminogen and control its activation. Since plasma contains basic carboxypeptidases, which remove carboxy-terminal lysines from protein substrates, we investigated if these enzymes are involved in the regulation of plasminogen binding sites. Plasma reduced plasminogen binding to cells, and this effect could be ascribed to the activity of the plasma carboxypeptidases. Purified carboxypeptidase N, which is constitutively active, and plasma carboxypeptidase B, which circulates as a zymogen, were both capable of significantly reducing plasminogen binding to cells. Dose titration experiments verified that plasma concentrations of either carboxypeptidase were sufficient to maximally affect plasminogen binding to cells. Furthermore, plasma carboxypeptidase B, but not carboxypeptidase N, reduced the rate of whole blood clot lysis induced by tissue-type plasminogen activator. These findings establish that plasma carboxypeptidases can modulate plasminogen binding to cells and control the rate of fibrinolysis. These functions delineate a novel role for the plasma carboxypeptidases in the regulation of the plasminogen system.

Blood Coagulation↗