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PubMed1973

Fibrinolysis associated with oncogenic transformation. Requirement of plasminogen for correlated changes in cellular morphology, colony formation in agar, and cell migration.

Fetal bovine and dog serum were selectively freed of plasminogen by affinity chromatography. The resulting serum as well as native and reconstituted serum (obtained by the addition of purified plasminogen to the plasminogen-depleted serum) were used to examine the role of plasminogen in (a) growth of normal and SV-40-transformed hamster embryo fibroblasts in liquid medium, (b) growth of SV-40-transformed hamster embryo fibroblasts in soft agar, (c) aggregation - a characteristic morphological change of SV-40-transformed hamster cells, and (d) migration of SV-40-transformed and control 3T3 cells from a monolayer into a "wound." The results demonstrated that exponential growth of both normal and transformed cells in liquid medium proceeded at the same rate in the presence or absence of plasminogen. In contrast, removal of plasminogen markedly depressed the plating efficiency of transformed cells in soft agar, eliminated their characteristic aggregation, and substantially reduced the extent of migration. The role of plasminogen and its activation in oncogenic transformation is discussed.

Agar↗
PubMed1991

Development of cross-reactive antibodies to plasminogen during the immune response to dengue virus infection.

The four serotypes of dengue virus (a mosquito-borne flavivirus) cause an acute febrile illness (dengue fever) or a more prolonged illness with plasma leakage resulting in hypovolemia (dengue hemorrhagic fever). Hemorrhage may accompany either. Epidemiologic data suggest a role for dengue antibodies in pathogenesis. Computer analysis revealed a 20-residue region of similarity in amino acid sequence between the dengue type 4 envelope glycoprotein (E) and a family of clotting factors, including plasminogen, the prime mediator of fibrinolysis. By use of synthetic peptides in ELISA, E antibodies that potentially bind plasminogen were detected in 75% of 40 Thai patients acutely infected with dengue virus type 1, 2, 3, or 4. Plasminogen cross-reactivity of dengue antibodies was shown to be specific for the related sites in E and plasminogen. The dengue E sequence with similarity to plasminogen is largely conserved within the currently known flavivirus E sequences. However, 15 Thai patients hospitalized for illness caused by Japanese encephalitis virus (a flavivirus not associated with hemorrhage) did not develop plasminogen-cross-reactive antibodies, and this finding correlated with failure of Japanese encephalitis virus antibodies to bind to the plasminogen-cross-reactive site in E.

Adolescent↗
PubMed1997

Collagen degradation induced by the combination of IL-1alpha and plasminogen in rabbit articular cartilage explant culture.

To investigate the effect of plasminogen on cartilage catabolism, we assessed collagen degradation in rabbit articular cartilage explants treated with or without plasminogen and interleukin-1alpha (IL-1alpha). The combination of IL-1 alpha and plasminogen induced rapid collagen degradation, amounting to more than 60% of the total collagen by day 7, while neither IL-1alpha nor plasminogen alone had any effect. To examine the mechanism of collagen degradation induced by IL-1alpha and plasminogen, the matrix metalloproteinases (MMPs) in the culture supernatants were examined by ELISA, Western blotting and gelatin zymography. We found that the treatment with IL-1alpha induced MMP-1, MMP-3, and MMP-9. In addition, plasminogen converted the pro form of MMPs into the active form. Both a tissue inhibitor of metalloproteinases-1 (TIMP-1) and a synthetic hydroxamate MMP inhibitor prevented this collagen release. These results suggest that plasminogen causes collagen degradation via activation of MMPs induced by IL-1alpha.

Amino Acid Sequence↗
PubMed1984

Plasminogens Tochigi II and Nagoya: two additional molecular defects with Ala-600----Thr replacement found in plasmin light chain variants.

Previous studies in our laboratories (Miyata, T., et al. (1982) Proc. Natl. Acad. Sci. U.S. 79, 6132-6136) showed that the structural defect in a hereditarily abnormal plasminogen, plasminogen Tochigi, is due to replacement of Ala by Thr at position 600 from the NH2-terminal end. In the present studies, two abnormal plasminogens, plasminogens Tochigi II and Nagoya, obtained from other family members were analyzed to identify the structural impairment in these molecules. Amino acid sequence analysis of one of the tryptic peptides isolated, respectively, from plasminogens Tochigi II and Nagoya indicated that in both cases, Ala-600 (equivalent to Ala-55 of the chymotrypsin numbering system) had been replaced by Thr. No other substitutions at the active site and substrate-binding site residues, namely, His-57, Asp-102, Ser-195, and Asp-189, were found in the plasmin light chain variants, indicating that all these residues are intact. Moreover, the NH2-terminal heptapeptide sequences of the plasmin light chain variants isolated from plasminogens Tochigi II and Nagoya were identical to the sequence determined for the normal control. These results indicate that the absence of proteolytic activity of both abnormal molecules is due to the same amino acid substitution as that of previously reported plasminogen Tochigi.

Alanine↗
PubMed1997

Asymptomatic coinheritance of heterozygous plasminogen deficiency and the factor VLeiden mutation.

Deficiency of plasminogen has been postulated by some authors as a possible thrombophilic abnormality, though this remains controversial. We have previously identified a cohort of individuals with plasminogen deficiency from a study to determine plasminogen levels within the general population. All were asymptomatic for thrombosis at initial identification. We followed this cohort over a 5-year period, with no venous thrombotic events recorded, although one patient did suffer a myocardial infarction. One family was identified with asymptomatic coinheritance of both plasminogen deficiency and the factor VLeiden mutation. There was no apparent venous thrombotic risk conferred upon any of our cohort of individuals by inheritance of plasminogen deficiency, and, in addition, the combination of the factor VLeiden mutation with plasminogen deficiency which was observed in three individuals did not result in thrombotic events. However, the cohort is small and we cannot entirely exclude plasminogen deficiency as a possible mild thrombophilic defect.

Adult↗
PubMed1999

The plasminogen activator inhibitor-1 gene, hypofibrinolysis, and osteonecrosis.

In 59 patients with osteonecrosis of the hip, four genes associated with thrombophilia or hypofibrinolysis along with coagulation tests were studied to determine the pathoetiologic associations of heritable coagulation disorders with osteonecrosis. Patients did not differ from healthy control subjects for the thrombophilic Factor V Leiden, prothrombin, or methylenetetrahydrofolate reductase mutations. The plasminogen activator inhibitor-1 gene was shifted toward homozygosity for the 4G polymorphism; 41% of patients with osteonecrosis were homozygous for the 4G/4G polymorphism versus 20% of 40 healthy control subjects. The gene product of the 4G polymorphism, hypofibrinolytic plasminogen activator inhibitor activity, was higher in patients than in control subjects (median 19.2 versus 6.3 U/mL); 61% of patients had high plasminogen activator inhibitor activity (> or = 16.4 U/mL) versus 5% of control subjects. Stimulated tissue plasminogen activator activity (inhibited by plasminogen activator inhibitor activity) was lower in patients than in control subjects (3.10 versus 5.98 IU/mL); 31% of patients had low stimulated tissue plasminogen activator activity (< 2.28 IU/mL) versus 3% of control subjects. Heritable hypofibrinolysis conferred by the 4G/4G mutation of the plasminogen activator inhibitor-1 gene seems to be a major pathoetiology of primary osteonecrosis.

Adult↗
PubMed2000

Plasminogen activation in focal cerebral ischemia and reperfusion.

In focal cerebral ischemia the plasminogen-plasmin system plays a role in the fibrinolysis of vessel-occluding clots and also in the proteolysis of extracellular matrix components, which potentially contributes to brain edema and bleeding complications. The authors investigated the plasminogen activation after middle cerebral artery occlusion with and without reperfusion (reperfusion intervals 9 and 24 hours) in rats by histologic zymography and compared areas of increased plasminogen activation to areas of structural injury, which were detected immunohistochemically. After 3 hours of ischemia, increased plasminogen activation was observed in the ischemic hemisphere. The affected area measured 5.2%+/-8.5% and 19.4%+/-30.1% of the total basal ganglia and cortex area, respectively. Reperfusion for 9 hours after 3 hours of ischemia led to a significant expansion of plasminogen activation in the basal ganglia (68.8%+/-42.2%, P < 0.05) but not in the cortex (43.0%+/-34.6%, P = 0.394). In the basal ganglia, areas of increased plasminogen activation were related to areas of structural injury (r = 0.873, P < 0.001). No such correlation was found in the cortex (r = 0.299, P = 0.228). In this study, increased plasminogen activation was demonstrated early in focal cerebral ischemia. This activation may promote early secondary edema formation and also secondary hemorrhage after ischemic stroke.

Animals↗
PubMed1997

Direct induction of complement activation by pharmacologic activation of plasminogen.

BACKGROUND: Complement activation occurs in patients with myocardial infarction treated with fibrinolytic agents and plays a critical role in reperfusion injury. This study was designed to determine whether pharmacologic activation of plasminogen directly induces complement activations. METHODS: Whole blood was incubated with plasminogen activators and the plasma was assayed for C3a levels as an indicator of complement activation. RESULTS: Therapeutic concentrations of tissue-type plasminogen activator, streptokinase, or urokinase increased C3a concentrations from a baseline of approximately 500 ng/ml to an average of 1300-1500 ng/ml with tissue-type plasminogen activator or urokinase, and to an average of approximately 4000 ng/ml with streptokinase (P < 0.01, versus baseline for all plasminogen activators). Plasminogen activation also enhanced complement activation induced by conventional complement activators. CONCLUSIONS: These results indicate that pharmacologic plasminogen activation may exacerbate reperfusion injury either by directly inducing complement activation or by enhancing the activation initiated by other mechanisms, or both.

Blood Specimen Collection↗
PubMed2004

Plasminogen activator inhibitor type 1: the two faces of the same coin.

PURPOSE OF REVIEW: Plasminogen activator inhibitor type 1 is the primary inhibitor of plasminogen activators. It is often bound to vitronectin, an abundant component of extracellular matrix in many tissues. The aim of this review is to discuss the contradictory results reported concerning the impact of plasminogen activator inhibitor type 1 expression in the kidney and in the vessel wall during pathological conditions. RECENT FINDINGS: First described as a 'bad guy' promoting the persistence of fibrin deposition and the evolution towards organ fibrosis, plasminogen activator inhibitor type 1 was recently reported to serve an unexpected protective role during fibrin-dependent diseases, such as experimental glomerulonephritis, and during aortic atherosclerosis. SUMMARY: Plasminogen activator inhibitor type 1 is not only an inhibitor of plasmin generation. Recent data suggest that plasminogen activator inhibitor type 1 is required for the regulation of plasminogen activator-dependent, plasmin-independent processes, and that its expression in vivo critically modulates inflammation, potentially by its capacity to occupy vitronectin binding sites.

Animals↗
PubMed1996

Plasminogen activator inhibitor 1 in thrombotic disease.

Impaired fibrinolytic function, mainly due to an elevation of plasma plasminogen activator inhibitor 1 concentration, is a common finding in patients with thrombotic disease. In patients subjected to hip surgery, preoperatively increased levels of plasminogen activator inhibitor 1 seem to be predictive of postoperative deep venous thrombosis. Several prospective studies of patients with angina pectoris or a past myocardial infarction have shown strong correlation between plasmatic plasminogen activator inhibitor 1 elevation and future cardiovascular events. However, before plasminogen activator inhibitor 1 can be regarded as a risk factor in the conventional epidemiologic sense, its relationship to myocardial infarction must be demonstrated in prospective studies of healthy populations. The regulation of plasminogen activator inhibitor 1 concentration in plasma is complex and at present not well understood. Multiple interactions with disturbances of both carbohydrate and lipoprotein metabolism are evident. Studies performed in cultured cells, transformed or natural, can be translated into human pathophysiology only with great caution. Both environmental and genetic factors seem to be of importance for the plasma plasminogen activator inhibitor 1 concentration. Platelet plasminogen activator inhibitor 1 seems to play a role in the resistance of platelet-rich thrombi to thrombolytic treatment.

Humans↗
PubMed1983

Plasminogen is present in the basal layer of the epidermis.

This study was undertaken to determine whether plasminogen was present within the epidermis. Cryostat sections of normal human skin were incubated with either whole rabbit antihuman plasminogen serum, the IgG fraction thereof, or the immune-specific IgG fraction thereof, purified by affinity chromatography on plasminogen-Sepharose. Standard indirect immunofluorescent techniques using rhodamine-conjugated goat antirabbit IgG were subsequently employed. Fluorescence was localized to the basal layer of the epidermis. Nonimmune serum and immune serum depleted of its specific anti-plasminogen IgG by prior affinity chromatography yielded negative results, demonstrating the specificity of staining for plasminogen. Our findings indicate that plasminogen is present within the epidermis, localized to the peripheral intracytoplasmic area of basal keratinocytes. This finding supports the hypothesis that a proteolytic event mediated by plasminogen activator with the subsequent generation of plasmin may be involved in normal keratinocyte physiology.

Cell Differentiation↗
PubMed1995

Identification of a plasminogen-binding motif in PAM, a bacterial surface protein.

Surface-associated plasmin(ogen) may contribute to the invasive properties of various cells. Analysis of plasmin(ogen)-binding surface proteins is therefore of interest. The N-terminal variable regions of M-like (ML) proteins from five different group A streptococcal serotypes (33, 41, 52, 53 and 56) exhibiting the plasminogen-binding phenotype were cloned and expressed in Escherichia coli. The recombinant proteins all bound plasminogen with high affinity. The binding involved the kringle domains of plasminogen and was blocked by a lysine analogue, 6-aminohexanoic acid, indicating that lysine residues in the M-like proteins participate in the interaction. Sequence analysis revealed that the proteins contain common 13-16-amino-acid tandem repeats, each with a single central lysine residue. Experiments with fusion proteins and a 30-amino-acid synthetic peptide demonstrated that these repeats harbour the major plasminogen-binding site in the ML53 protein, as well as a binding site for the tissue-type plasminogen activator. Replacement of the lysine in the first repeat with alanine reduced the plasminogen-binding capacity of the ML53 protein by 80%. The results precisely localize the binding domain in a plasminogen surface receptor, thereby providing a unique ligand for the analysis of interactions between kringles and proteins with internal kringle-binding determinants.

Amino Acid Sequence↗
PubMed1981

Primary structure of porcine plasminogen. Isolation and characterization of CNBr-fragments and their alignment within the polypeptide chain.

The single polypeptide chain of native plasminogen (molecular weight approx. 90000) after CNBr-cleavage and gel filtration (Sephadex G-75) yielded a high molecular weight core fraction of fragments linked by disulfide bridges and three fragments of lower molecular weight (N-terminal and C-terminal CNBr-fragments and dodecapeptide). From the reduced and S-carboxamidomethylated core fraction an additional seven fragments with molecular weights between 2000 and 38000 were obtained. The CNBr-fragments were aligned in the porcine plasminogen polypeptide chain according to sequence homologies with the known primary structure of human plasminogen. Due to the lack of two methionine residues in kringle 1 and in the N-terminal part of the light chain region and to an additional methionine residue in kringle 2 the CNBr-fragment pattern differs from that of human plasminogen. Affinity chromatography of elastase-digested, native plasminogen yielded three fragments with intact lysine binding sites, originating from the heavy chain region and a non-adsorbable fragment, corresponding to human 'mini'-plasminogen. This fragment was converted to urokinase into a proteolytically active protein which served for the isolation of the porcine plasmin light chain. With the aid of the fragments produced by the CNBr and elastase cleavage approx. 350 residues were sequenced, of which about 80% showed identity with the sequence of human plasminogen. This percentage varied depending on the region of the molecule, with the highest extent of identity (80--90%) found in the analyzed kringles 2 and 4.

Amino Acid Sequence↗
PubMed1982

Messenger RNA for human tissue plasminogen activator.

A human melanoma cell line (Bowes), which secretes extrinsic (tissue-type) plasminogen activator, was used as a source for the preparation of mRNA for extrinsic plasminogen activator. The cells were lysed and total RNA was extracted with the phenol method. A poly(A)-rich RNA fraction was isolated by affinity chromatography on oligo(dT)-cellulose. This preparation was translated by oocytes into (a) protein(s) that had biological activity in the assay for extrinsic plasminogen activator. On sucrose gradient centrifugation the translatable fraction of the RNA migrated with a sedimentation coefficient of approximately 19 S, a value compatible with the molecular weight of extrinsic plasminogen activator (70 000). The translation product was characterized as being similar to or identical with authentic extrinsic plasminogen activator by the following criteria: (a) serological cross-reactivity with purified extrinsic plasminogen activator in neutralization and immunoprecipitation reactions; (b) plasminogen dependency of fibrinolytic activity and (c) apparent molecular weight of 70 000 on sodium dodecyl sulphate/polyacrylamide gel electrophoresis.

Animals↗
PubMed1993

Plasminogen activator inhibitor: a risk factor for myocardial infarction in diabetic patients.

OBJECTIVE: To determine whether diabetic patients admitted with acute myocardial infarction have impaired fibrinolytic activity due to raised plasminogen activator inhibitor compared with non-diabetic patients. SETTING: A district general hospital. PATIENTS: 90 non-diabetic and 38 diabetic patients admitted with acute myocardial infarction. RESULTS: Both plasminogen activator inhibitor activity and antigen were significantly higher in diabetic than in non-diabetic patients (24.7 (6.8) v 18.5 (6.8) AU/ml; p = 0.0001 and 64.2 (range 13.1 to 328.8) v 38.5 (range 10.9 to 173.7 ng/ml; z = 3.3; p = 0.0008) with a positive correlation between activity and antigen (rs = 0.51; p = 0.0001). In both groups, activity and antigen concentrations were significantly higher than in diabetic and non-diabetic subjects without coronary artery disease (p = 0.002 to 0.0001 for each comparison). Plasminogen activator inhibitor activity correlated significantly with admission plasma glucose (r = 0.32; p = 0.0001), glycated haemoglobin (r = 0.32; p = 0.0001), admission plasma insulin (rs = 0.48; p = 0.001), and Killip grade of heart failure both on admission (rs = 0.27; p = 0.001) and on discharge (rs = 0.22; p = 0.006), but not with cumulative creatine kinase MB isoenzyme release (rs = -0.08). There were similar but weaker correlations between tissue plasminogen activator antigen and admission plasma glucose, glycated haemoglobin, and insulin. In 18 patients (12 non-diabetic and six diabetic) plasminogen activator inhibitor activity was measured between six and 12 months (8.3 (1.6)) after the acute infarct and remained similar to activity on admission (24.8 (1.9) AU/ml (NS) for diabetic and 17.9 (6.9) AU/ml (NS) for non-diabetic patients) and was still significantly higher in diabetic than in non-diabetic patients (p = 0.007). CONCLUSION: These results show that diabetic patients have higher plasminogen activator inhibitor activity than non-diabetic patients both on admission with acute myocardial infarction and at follow up six to 12 months later. Raised plasminogen activator inhibitor activity may predispose diabetic patients to myocardial infarction and may also impair pharmacological and spontaneous reperfusion after acute myocardial infarction thus contributing to the poor outcome in these subjects.

Aged↗
PubMed2005

Angiostatin and plasminogen share binding to endothelial cell surface actin.

Previous studies from this laboratory have demonstrated that plasminogen binds to endothelial cell surface-associated actin via its kringles in a dose-dependent and specific manner. The purpose of this study was to determine whether angiostatin, a proteolytic fragment of plasminogen, shares binding properties with plasminogen. Our results indicated that like plasminogen, angiostatin bound to actin in a time-, concentration-, and kringle-dependent manner. Furthermore, this binding was significantly inhibited by excess plasminogen, suggesting that both proteins shared binding motifs on the actin molecule. Fluorescence studies demonstrated that angiostatin bound to intact endothelial cells through its kringles, and this binding was also inhibited by plasminogen but not by unrelated proteins. Ligand blot analyses on endothelial cell lysates indicated that angiostatin interacted with a 42 kDa protein, which was identified as actin. Furthermore, an anti-actin antibody inhibited binding of angiostatin to endothelial cells by approximately 25%. These results suggest that angiostatin and plasminogen share binding to endothelial cell surface actin and, therefore, that angiostatin has the potential to inhibit plasmin-dependent processes such as cell migration-movement.

Actins↗
PubMed1983

Hormonal influences on formation of plasminogen activator by cultured testis tubule segments at defined stages of the cycle of the seminiferous epithelium.

We confirm that basal rates of formation of plasminogen activator by cells in cultured tubule segments at stages of the cycle associated with spermiation (stages VII and VIII) are higher than those by cells in tubule segments at any other stages of the cycle of the seminiferous epithelium. We demonstrate that addition of cAMP derivatives or follicle-stimulating hormone in the presence of a phosphodiesterase inhibitor results in a large stimulation of plasminogen activator formation by tubule segments at all stages of the cycle. The greatest percentage increase (approximately 100-fold) is observed in cells in tubule segments having lowest basal rates of plasminogen activator formation (stages IX-VI). Even under stimulated conditions, however, the amounts of plasminogen activator produced by cultured tubule segments at stages VII and VIII remain greater than those produced by cultured tubule segments at other stages of the cycle, and these differences persist during organ culture for 48 h. Insulin and testosterone do not alter rates of formation of plasminogen activator. We conclude that Sertoli cells, the primary source of formation of plasminogen activator in the testis, are metabolically heterogeneous in the seminiferous tubule and that the germ cell association patterns in various stages of the cycle modulate Sertoli cell functions. We discuss the data in relation to the tissue restructuring within the seminiferous tubule which occurs during spermatogenesis and the possible role of plasminogen activator in these processes.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Characterization of plasminogen binding to human capillary and arterial endothelial cells.

Phenotypic diversity of endothelial cells that line the various vascular spaces has been well established. However, it is not known if biochemical differences also exist, particularly in the numbers of receptors for plasma proteins. Equilibrium binding techniques were used to assess potential differences in the binding of 125I-labelled plasminogen to cultured human umbilical arterial endothelial cells and capillary endothelium, as compared with umbilical venous cells. The kinetic behaviour of plasminogen binding to all three types of cells was similar, with optimal binding occurring between 20 and 30 min of incubation. Binding of plasminogen to arterial, capillary, and venous cells was concentration dependent and reversible upon addition to excess unlabelled plasminogen. Scatchard analyses showed that artery, capillary, and venous endothelial cells all possess low affinity sites for plasminogen with Kd values of 0.30 +/- 0.07, 0.40 +/- 0.06, and 0.40 +/- 0.08 microM, respectively. Vein cells also possess an additional higher affinity binding site with a Kd of 0.07 +/- 0.01 microM, exhibiting a 6-fold greater affinity for plasminogen than the lower affinity sites on capillary and arterial endothelial cells. Assuming a stoichiometry of 1:1 for binding, the data indicate that arterial and capillary endothelial cells contain approximately 4.2 (+/- 0.9) x 10(6) and 4.1 (+/- 0.6) x 10(6) plasminogen receptors per cell. Venous cells contain both low and high density binding sites with 6.2 (+/- 0.8) x 10(6) and 12.4 (+/- 2.4) x 10(6) sites per endothelial cell. The presence of a higher affinity site on vein cells, but not on artery or capillary cells, may signal functional differences relating to fibrinolytic activity on the surface of these cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Binding Sites↗