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PubMed1991

Increased plasma plasminogen activator inhibitor 1 levels. A possible link between insulin resistance and atherothrombosis.

According to recent prospective studies, hypofibrinolysis due to elevated plasma plasminogen activator inhibitor 1 levels appears to be an independent risk factor for myocardial reinfarction in men, and hyperinsulinaemia, a major indicator of insulin resistance is considered as a risk factor for coronary disease. It has recently been shown that insulin resistance is accompanied by an increased plasma plasminogen activator inhibitor 1 concentration: A significant correlation coefficient was demonstrated between plasminogen activator inhibitor 1 and fasting plasma insulin in the normal population, in obese subjects, in Type 2 (non-insulin-dependent) diabetic patients and in angina pectoris. Attempts to decrease insulin resistance such as fasting, diet, or administration of an oral anti-diabetic drug such as Metformin induced a parallel decrease in plasma insulin and plasminogen activator inhibitor 1 levels. This inhibitor is produced by endothelial cells and by hepatocytes in culture. Plasminogen activator inhibitor 1 synthesis by hepatocytes in culture was stimulated by an increasing insulin concentration, or low density lipoproteins, whereas the endothelial cell synthesis was stimulated by very low density lipoproteins especially when they were obtained from hypertriglyceridaemic patients. Therefore, a direct effect of insulin or lipoprotein changes on the cells which synthesize plasminogen activator inhibitor 1 could be responsible for its increased plasma concentration in insulin resistance states. The increase in plasma plasminogen activator inhibitor 1 levels linked to hyperinsulinaemia is a tempting partial explanation for the association between insulin resistance and coronary disease.

Arteriosclerosis↗
PubMed2000

Ligneous conjunctivitis in a girl with severe type I plasminogen deficiency.

BACKGROUND: Ligneous conjunctivitis is a rare form of chronic recurrent pseudomembranous disease and may be associated with systemic membranous pathological changes. Recently ligneous conjunctivitis has been linked to severe type I plasminogen deficiency. We report on a patient with plasminogen deficiency and severe bilateral ligneous conjunctivitis. A new treatment approach and its outcome in this patient are described. CASE REPORT: We present the case of a 9-month-old Turkish girl with massive swelling of the eyelids and hard white pseudomembranes on both lids. The conjunctival smear was positive for Streptococcus pneumoniae. The clinical diagnosis was: ligneous conjunctivitis with superinfection. Histological investigation showed fibrin as major component of the pseudomembranes. The coagulation analyses revealed decreased plasminogen activity (<5%; normal 80-120%) and decreased plasminogen antigen (<0.4 mg/dl; normal 6-25 mg/dl). The failure of surgical therapy led to the attempt at treatment with intravenous lys-plasminogen. A significant improvement of the ocular symptoms occurred; stabilization with no recurrent pseudomembranes could be achieved for 6 months after treatment. DISCUSSION: The initial amelioration of symptoms in our patient after systemic replacement therapy confirms the etiological importance of plasminogen deficiency in the development of ligneous conjunctivitis. Curative treatment of ligneous conjunctivitis is still not available. However, intravenous application of plasminogen offers new possibilities in therapy, although long-term treatment seems necessary.

Conjunctiva↗
PubMed1998

A significant relationship between plasminogen activator inhibitor type-1 and lipoprotein(a) in non-insulin-dependent diabetes mellitus without complications.

We previously found a relationship between plasminogen activator inhibitor type-1 and lipoprotein(a) in non-insulin-dependent diabetes mellitus and hypothesized that this could be due to a compensatory mechanism able to lower the risk of hypofibrinolysis found in type II diabetes mellitus. The aims of the present study were: (1) to confirm the association between plasminogen activator inhibitor type-1 and lipoprotein(a) in a different group of non-insulin-dependent diabetes mellitus patients and (2) to investigate whether the association could be related to diabetic complications. Other vascular risk factors able to influence fibrinolytic parameters such as glycemia, obesity, hypertension, dyslipidemia, and oxidative stress were also considered. Sixty-six non-insulin-dependent diabetes mellitus patients without diabetic complications (48 men, 18 women), 45 non-insulin-dependent diabetes mellitus patients with complications (21 men, 24 women), and 31 control subjects (17 men, 14 women) were studied. Plasma concentrations of lipoprotein(a), plasminogen activator inhibitor type-1 antigen and activity, and the main parameters of lipo- and glycometabolic balance were determined. Antioxidant defense was assayed as oxygen radical absorbance capacity of serum. Statistically significant differences among controls and the two diabetic groups were found for fasting glucose, cholesterol, triglycerides, and oxygen radical absorbance capacity of serum, while no statistically significant differences were evident for plasminogen activator inhibitor type-1 antigen and activity and lipoprotein(a). Regression analysis of log plasminogen activator inhibitor type-1/lipoprotein(a) showed a significant correlation only in diabetic patients without complications (r = -0.57, P < 0.001). These results show that a relationship between plasminogen activator inhibitor type-1 and lipoprotein(a) is characteristic of a diabetic population without complications, supporting the suggestion that this relationship could be a compensatory mechanism of the fibrinolytic system to limit the risks of hypofibrinolysis. A lack or a loss of capacity to balance lipoprotein(a) and plasminogen activator inhibitor type-1 could contribute to the pathogenesis of the diabetic complications.

Adult↗
PubMed1989

A chromogenic assay for the detection of plasmin generated by plasminogen activator immobilized on nitrocellulose using a para-nitroanilide synthetic peptide substrate.

A direct solid phase chromogenic assay has been developed for the detection of plasmin (EC 3.4.21.7), generated by the interaction of a nitrocellulose-bound plasminogen activator, using the plasmin specific tripeptide substrate, H-D-valyl-leucyl-lysine - p-nitroaniline. para-Nitroaniline released by the cleavage of the lysine - p-nitroaniline bound by plasmin was derivatized to its diazonium salt and subsequently coupled to N-1-napthylethylenediamine in situ to form a diazoamino of an intense red color at the site of the plasminogen activator. This method was used to assay for the streptococcal plasminogen activator, streptokinase, not only in crude bacterial supernatants, but also to detect streptokinase secreted by individual bacterial colonies. In addition, this solid phase assay was used to identify monoclonal antibodies specific for streptokinase which could inhibit the activation of human plasminogen by streptokinase. This method also permitted simultaneous immunological and biochemical identification of the plasminogen activator, thus permitting unequivocal comparative observations. This assay is quantitative and sensitive to nanogram amounts of activator comparable to those obtained with soluble assays. This method may also be applicable for the detection of other plasminogen activators, such as tissue plasminogen activator, urokinase, and staphylokinase, and also for the detection of immobilized proteases which can cleave other substrates derivatized with p-nitroaniline. The reagents used in this assay are inexpensive and easy to prepare.

Antibodies, Monoclonal↗
PubMed1991

Plasminogen activator in human periodontal health and disease.

Plasminogen activators, proteases associated with the fibrinolytic system, also play a major part in extravascular processes such as tissue remodelling, cell migration and activation of prohormones, growth factors and other proteases. It is likely that plasminogen activators participate in the pathophysiology of periodontal disease. Plasminogen activator has been identified in human gingival crevicular fluid in a concentration 100-fold greater than in plasma. The local activity of plasminogen activator in gingival tissues was examined and changes detected in its distribution in relation to the extent of disease. Frozen sections from human gingival biopsies were overlaid on fibrin-coated slides; tissue-type plasminogen activator activity was found in all samples. Focal activity was observed in healthy tissue, originating from the most superficial cells of the junctional epithelium. Biopsies of clinically healthy sites obtained 6 weeks after treatment for periodontitis also showed epithelial plasminogen activator activity localized to this area. In contrast, in diseased tissue the entire epithelium lining the periodontal pocket showed activity. This differential pattern of activity in health and disease is consistent with the hypothesis that plasminogen activator is a modulator of periodontal homeostasis.

Gingiva↗
PubMed1980

Purification and characterization of human vascular plasminogen activator.

The vascular tree of the legs of human corpses was perfused with 0.15 M NaCl, and eluted with 2 M KSCN and finally with 0.15 M NaCl. The average total activity of human vascular plasminogen activator and protein eluted per leg was 29 800 Ploug units and 8.3 g respectively. Fibrin-Sepharose adsorbed the plasminogen activator activity, which could be eluted with 2 M KSCN. A small column containing from 0.5--1.9 ml of phenyl-Sepharose, normally coupled directly to the outlet of the fibrin-Sepharose column, adsorbed all the plasminogen activator activity. Elution of this hydrophobic matrix yielded a plasminogen activator preparation 17% pure judging from sodium dodecyl sulphate polyacrylamide gel electrophoresis. By this method human vascular plasminogen activator was found to have an Mr of 60 000. Upon reduction, two bands of Mr 30 000 and 31 000 were estimated. Human vascular plasminogen activator could be inhibited by diisopropylfluorophosphate. Isoelectric focusing yielded four major bands with the isoelectric points of 6.9, 7.4, 8.0 and 8.6. Human vascular plasminogen activator was found to be a relatively stable protein in purified form.

Chromatography, Affinity↗
PubMed1992

Microglia isolated from rat brain secrete a urokinase-type plasminogen activator.

In a previous study, we found particular proteases which degrade myelin basic protein (MBP) in a conditioned medium of cultured rat brain microglia. The MBP degrading activity in microglial-conditioned medium (Mic-CM) increased markedly in the presence of plasminogen. By Sephadex G-150 column chromatography, plasminogen-dependent MBP degrading activity was eluted at the position of about 47 kDa and 28 kDa. Furthermore slight plasminogen-dependent protease activity in the presence of fibrin (tissue plasminogen activator activity) was detected at a molecular weight of about 68 kDa. The two molecular forms (47 kDa and 28 kDa) of plasminogen-dependent protease were demonstrated by casein-zymography, and it was suggested that they were urokinase type-plasminogen activators (uPA). This suggestion was confirmed by immunoblotting using anti-uPA antiserum. The unique 28 kDa type was considered to be produced from the 47 kDa form by limited proteolysis. Secretion of PA from microglia was demonstrated by cell zymography. In contrast, significant secretion of plasminogen activator inhibitor could not be detected in the Mic-CM. In addition, lipopolysaccharide significantly decreased the secretion of PA from microglia, while interleukin-1 and basic fibroblast growth factor enhanced the secretion.

Animals↗
PubMed1986

Differential secretion of plasminogen activator activity by postsurgical activated macrophages.

Macrophage functions during postsurgical tissue repair include secretion of neutral proteases like plasminogen activator. Accordingly, we studied the differential secretion of plasminogen activator by postsurgical macrophages. Rabbits underwent resection and reanastomosis of their small bowel (three rabbits/time group). Postoperatively (up to 28 days), they underwent a second laparotomy for collection of ascites cells by lavage. Cells were incubated with culture medium containing 10% acid-treated fetal calf serum. After 2 days, the medium was removed (1-2 days media, M1) and replaced for 2 more days (3-4 days media, M2). Plasminogen activator activity of the medium (M1 and M2) was determined using a modified indirect solid-phase radioassay. The specific plasminogen activator activity (plasminogen-dependent-plasminogen-independent activator activity) in M1 was 43 mPU/10(6) cells in nonsurgical control rabbits. Exudative cells on Day 1 had less activity than control, and by Day 5, the activity significantly increased to 290% of control levels, reaching peak value on Day 14 (360%). The specific plasminogen activator activity in M2 was 310 mPU/10(6) cells in nonsurgical control media. Exudative cells on Day 1 had less activity than control, while, on Days 3-7, they were the same as control. By day 10, specific activity significantly increased to peak levels 188% of control and then gradually decreased. Since a marked increase in the number of macrophages parallels the increase in these metabolic activities through postsurgical Day 10, postsurgical activated macrophages appear to play an important role in peritoneal healing.

Animals↗
PubMed1992

Adsorption of plasminogen from plasma to lysine-derivatized polyurethane surfaces.

The adsorption of plasminogen, the principal protein of the fibrinolytic pathway in blood, to a number of solid surfaces from plasma was investigated. This study forms part of a larger project to develop a fibrinolytic surface for blood-contacting applications. Polyurethanes incorporating lysine residues were developed in an attempt to promote selective adsorption of plasminogen from plasma through lysine-binding sites in the plasminogen molecule. The adsorption of plasminogen to these surfaces as well as to glass, 'conventional' polyurethanes and precursor sulphonated polyurethanes was investigated. Adsorption from citrated human plasma diluted with isotonic Tris buffer (pH 7.4) was measured under static conditions at room temperature using radioiodinated plasminogen. The following trends were observed. (1) Adsorption increases monotonically with increasing plasma concentration and there is no suggestion of transient adsorption (Vroman effect) on any of the surfaces studied. (2) Sulphonate groups appear to have a strong effect on plasminogen adsorption as was found previously for adsorption from buffer. (3) The lysine-derivatized material having the highest lysine content may show a slight increase in plasminogen binding affinity compared to its sulphonated precursor.

Adsorption↗
PubMed1993

Plasminogen promotes the development of rat mesencephalic dopaminergic neurons in vitro.

In order to investigate the physiological significance of plasminogen, which is produced by and secreted from microglia, we determined the effects of plasminogen on the development of primary cultured mesencephalic neurons from 16-day-old embryonic rats. Plasminogen markedly increased dopamine uptake and the dopamine content of cultured neurons. Furthermore, the number of mesencephalic dopaminergic neurons, which was determined by immunostaining with tyrosine hydroxylase antibody, was significantly increased in the presence of plasminogen. However, plasminogen had only a slight effect on gamma-aminobutyric acid (GABA) uptake and glutamic acid decarboxylase activity in mesencephalic neurons. The effect on dopaminergic neurons was also observed in the culture in the presence of cytosine arabinoside. In addition, plasminogen had no effect on the number of glial fibrillary acidic protein-positive cells. These results suggest that plasminogen acts directly on neurons and enhances the development of dopaminergic neurons in a rather selective manner.

Animals↗
PubMed1989

Further characterization of the binding of plasminogen to heparin: evidence for the involvement of lysine residues.

We have previously demonstrated that the heparin-binding site of plasminogen is located in Val442-plasminogen region (kringle 5 domain plus light (B) chain) (Soeda, S., Kakiki, M., Shimeno, H., and Nagamatsu, A. (1987) Biochim. Biophys. Acta 916, 279-287). The chemical modification of Val442-plasminogen with a lysine reagent, pyridoxal 5'-phosphate (PLP), and sodium borohydride resulted in the incorporation of 8-10 PLP moieties per molecule of the zymogen. This PLP-labeled zymogen had no affinity for a heparin-Sepharose column, whereas the non-labeled one bound to the column. Modification in the presence of heparin decreased the extent of labeling by 1-2 mol of PLP per mol of Val442-plasminogen. To further examine the binding site of plasminogen to heparin, functionally active A and B chains were separated from Lys-plasmin after mild reduction and S-carboxymethylation. Only B chain possessed affinity for heparin-Sepharose. Furthermore, plasmin(ogen) bound to heparin was protected from alpha 2-antiplasmin inhibition. These results indicate that one or two lysine residues located in the catalytic region (B chain) of plasmin(ogen) are essential to heparin binding, and that the binding of plasminogen to heparin or heparin-like substance in extracellular matrix environments may be important for the localization and activation of plasminogen and for the prolongation of the resultant plasmin activity.

Binding Sites↗
PubMed1986

Calcium regulation of tissue plasminogen activator and prostaglandin biosynthesis in HeLa cells.

Phorbol 12-myristate 13-acetate, 1-20 nM, induced the synthesis in HeLa cells of a 65 200 Mr tissue-type plasminogen activator, and of prostaglandin E2. Omission of Ca2+ from the incubation medium inhibited the induction of plasminogen activator synthesis by 40-60% and abolished the induction of prostaglandin E2 synthesis. Maximal plasminogen activator synthesis could be maintained at extracellular Ca2+ concentrations of approx. 0.1 mM, while maximal prostaglandin synthesis required at least 0.45-0.9 mM Ca2+. The induction of each factor was inhibited by 10-100 microM 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8), an inhibitor of intracellular C2+ mobilization. Prostaglandin synthesis, but not plasminogen activator synthesis, was also inhibited by 10-100 microM verapamil and nifedipine, which inhibit intracellular Ca2+ uptake via the so-called 'slow-channels' and by 0.5-10 microM trifluoperazine, an inhibitor of calmodulin. Neither plasminogen activator synthesis nor prostaglandin synthesis were stimulated by 5-50 microM 1-oleoyl-2-acetylglycerol or 1-250 microM 1,2-dioctanoylglycerol, alone and in combination with 50 nM-1 microM ionophore A23187. These results indicate that the synthesis of plasminogen activator and prostaglandins in HeLa cells is Ca2+-dependent, and that the Ca2+ requirements for each process are not identical. Thus, Ca2+ regulation of the production of tissue plasminogen activator and prostaglandin E2 occurs at multiple points in their biosynthetic pathways.

Calcimycin↗
PubMed1983

Importance, localization and functional properties of the cell-associated form of plasminogen activator in mouse peritoneal macrophages.

In inflammatory macrophages, plasminogen activator exists in two active forms, a soluble form released into the extracellular medium and a cell-associated form. This communication describes some properties of the cellular form of plasminogen activator, in intact macrophages and in cell lysates. Cellular plasminogen activator is a membrane protein, associated with the outer face of the plasma membrane; in intact macrophages, it participates in the activation of exogenous plasminogen and, thus, has to be considered as an ectoenzyme. A plasminogen activator activity can be detected in cell lysates (macrophage monolayers lysed in 0.1% Triton X-100) only when plasmin production is followed by the use of small synthetic substrates because a soluble inhibitor, released during extraction, blocks plasmin fibrinolytic activity. In these lysates, plasminogen activator molecules exist as high molecular weight unstable complexes exhibiting a high affinity for plasminogen.

Animals↗
PubMed1990

Characterization of the cDNA coding for mouse plasminogen and localization of the gene to mouse chromosome 17.

A full-length cDNA coding for mouse plasminogen has been isolated and characterized. The cDNA is 2720 bp in length (excluding the poly(A) tail) and contains a 24-bp 5' noncoding region, an open reading frame of 2436 bp, and a 3' noncoding region of 257 bp. The open reading frame codes for 812 amino acids and includes a signal peptide that is likely 19 amino acids in length and the mature protein of 793 amino acids. The calculated Mr of mouse plasminogen is 88,706 excluding carbohydrate. There are two potential N-linked carbohydrate addition sites; one of which is glycosylated in human, bovine, and porcine plasminogens. Mouse plasminogen was found to contain two additional amino acids compared to the human protein. In addition, mouse and human plasminogens were found to be 79 and 76% identical at the protein and DNA levels, respectively. Analysis of the segregation of two allelic forms, Plgb and Plgd, of plasminogen DNA in three sets of recombinant inbred strains has allowed the localization of the mouse plasminogen gene to the proximal end of mouse chromosome 17 within the t complex and close to the locus D17Rp17. The Plg gene is deleted in the semidominant deletion mutant, hair-pintail (Thp).

Alleles↗
PubMed2005

The role of carbohydrate side chains of plasminogen in its activation by staphylokinase.

Kinetic parameters (k(Pg) and K(Pg)) were determined for activation of Glu-plasminogen (Glu-Pg) and Lys-plasminogen (Lys-Pg) type I (with N-linked carbohydrate chain at Asn-289) and type II (with unsubstituted Asn-289) by plasmin-staphylokinase (Pm-STA) complex. The K(Pg) values for Glu-Pg I and Lys-Pg I (17.1 and 11.2 microM, respectively) were higher than those for Glu-Pg II and Lys-Pg II (14.9 and 5.4 microM, respectively), while only minor differences in the k(Pg) values were observed between plasminogens type I and type II. Soluble fibrin significantly increased the k(Pg)/K(Pg) values for activation of all four plasminogens due to a decrease in the K(Pg) values but did not alter the k(Pg) values. However, the activation of plasminogens type I was stimulated by fibrin lesser degree than that of plasminogens type II. These findings indicate that N-glycosylation of kringle 3 of plasminogen decreases the stability of Pm-STA-Pg ternary enzyme-substrate complex in solution as well as interferes with its formation and rearrangement on the fibrin surface.

Enzyme Activation↗
PubMed2003

Plasminogen-induced IL-1beta and TNF-alpha production in microglia is regulated by reactive oxygen species.

Microglia, major immune effector cells in the central nervous system, become activated during brain injury. In this study we showed that the blood component plasminogen/plasmin activates microglia. Plasminogen-induced IL-1beta, TNF-alpha, and iNOS mRNA expression in primary cultured rat microglia and BV2 murine microglial cells. Plasmin caused a similar response. Serine protease inhibitors suppressed both plasminogen- and plasmin-induced IL-1beta and TNF-alpha expression, indicating the importance of serine protease activity in plasminogen/plasmin activation of microglia. Reactive oxygen species (ROS) appeared to play an important role in plasminogen-induced microglial activation, with ROS being generated within 15min of plasminogen treatment, and antioxidants (100 microM trolox and 10mM NAC) reducing IL-1beta and TNF-alpha expression in plasminogen-treated cells. Furthermore, plasminogen stimulated CREB and NF-kappaB DNA binding activity, and this activation was also reduced by trolox and NAC. These results suggest that plasminogen activates microglia via stimulation of ROS production.

Animals↗
PubMed2005

Angiostatin directly inhibits human prostate tumor cell invasion by blocking plasminogen binding to its cellular receptor, CD26.

Previous studies demonstrate that one of the six plasminogen type 2 glycoforms, plasminogen 2epsilon, enhances invasiveness of the 1-LN human prostate tumor cell line in an in vitro model. Binding of plasminogen 2epsilon to CD26 on the cell surface induces a Ca(2+) signaling cascade which stimulates the expression of matrix metalloproteinase-9, required by these cells to invade Matrigel. We now report that angiostatin, a fragment derived from plasminogen which prevents endothelial cell proliferation, is also a potent, direct inhibitor of 1-LN tumor cell invasiveness. We studied the effect of individual plasminogen 2 glycoform-derived angiostatins and found that only angiostatin 2epsilon binds to CD26 on the surface of 1-LN cells at a site also recognized by plasminogen 2epsilon. As a result, the plasminogen 2epsilon-induced Ca(2+) signaling cascade is inhibited, the expression of matrix metalloproteinase-9 is suppressed, and invasion of Matrigel by 1-LN cells is blocked. Angiostatin 2epsilon is also the only angiostatin glycoform which is able to inhibit in vitro endothelial cell proliferation and tubule formation. These studies suggest that, in addition to its ability to inhibit tumor vascularization, angiostatin 2epsilon may also directly block tumor metastasis.

Angiostatins↗
PubMed1994

The content of urokinase-type plasminogen activator and tumor recurrence in superficial bladder cancer.

The contents of urokinase-type plasminogen activator were estimated in superficial bladder cancer from 42 patients undergoing transurethral resection for the first time. Tumor recurred in 11 of 16 patients (68.8%) with high urokinase-type plasminogen activator content (8 ng. urokinase-type plasminogen activator per mg. protein and more) and in 12 of 26 (46.2%) with low urokinase-type plasminogen activator content. In the high content group 8 patients (50%) had disease progression compared to 2 (7.7%) in the low content group (p < 0.01). The progression rates in the high urokinase-type plasminogen activator group with stage pTa disease or tumors more than 1 cm. large were significantly higher than those in the low urokinase-type plasminogen activator group (p < 0.05). The recurrence and progression rates in the high content group with stage pT1, grades 2 and 3, single and multiple tumors, and tumors less than 1 cm. large were higher than those in the low content group. The progression-free survival rate in the high content group was significantly lower than that in the low content group (p < 0.005). In conclusion, urokinase-type plasminogen activator content may be a useful marker to predict recurrence and progression of superficial bladder cancer.

Aged↗