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PubMed1988

Effectiveness of intraarterial plasminogen application in combination with percutaneous transluminal angioplasty (PTA) or catheter assisted lysis (CL) in patients with chronic peripheral occlusive disease of the lower limbs (POL).

The accepted correct procedure for treating occlusive arterial diseases includes surgical disobstruction, CL as well as PTA. Combined non-surgical strategies are effective in about 60% of these patients. However, a high risk of rethrombosis despite from the prophylaxis with anticoagulants like heparin or antiplatelet drugs like ASA is proven, especially in patients with multi-segmental stenosis as well as in patients with extensive narrowing of the arteries. In these cases primary lesions (endangitis obliterans) or secondary lesions of the endothelium cause local depletion of plasminogen in the endothelium. Independent of the method used for reopening the vessel in these patients, a significant progression of the vessel disease and a high rethrombosis rate during longterm follow-up is observed. These results lead us to apply plasminogen locally to decrease the rate of rethrombosis. In patients suffering from stage III-IV (La Fontaine) including patients with multi-segmental stenosis as well as extended narrowing of the artery, PTA in combination with CL was performed. The catheter was placed as near as possible to the thrombus. In some cases the 'fibrinolyticum' could be injected directly into the thrombus. In these cases a bolus of 4,000 U/ml was locally infused, otherwise 1.0-1.5 million U urokinase per 24 hrs. were locally infused with heparin. In 28% (22 patients) no sufficient clinical response occurred using this combined therapy and plasminogen was applied locally. The following criteria supported our decision to include the patients in this study: 1. Insufficient response occurring after 12-24 hrs. of local infusion. 2. Following 6 bolus injections no reopening of the vessel occured within 60 minutes or the clinical response was insufficient due to rethrombosis. 3. Insufficient effects of lysis therapy after 2 hours and contraindication for a systemic fibrinolytic therapy (e.g. hypertension, age, etc.). 1,000 U plasminogen per ml were infused locally or 2,000 U up to 5,000 U plasminogen (in 5 to 10 ml 0.9% saline) were infused slowly (2-4 minutes infusion time) into the catheter in these patients 10 minutes after unsuccessful treatment with local urokinase therapy. Five minutes after administering plasminogen local intraarterial fibrinolytic therapy with urokinase was continued. No severe side effects due to this therapy were observed, although some patients suffered from acute pains in the peripheral segments of the arteries occurring immediately after infusion of plasminogen. In 16 of 22 patients a complete recanalization occurred and in 3 patients a satisfying clinical improvement was observed.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed2003

Plasmin generation dependent on alpha-enolase-type plasminogen receptor is required for myogenesis.

Plasmin is a potent extracellular protease specialized in the degradation of fibrin (fibrinolysis). Active plasmin is generated by proteolytic activation of the zymogen plasminogen (Plg) by urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA). Alpha-enolase constitutes a receptor for plasminogen on several leukocyte cell types, serving to localize and promote plasminogen activation pericellularly. However, a role for a -enolase-type plasminogen receptor (PlgR) in myogenesis has never been demonstrated. In this study, we show that C2C12 mouse myoblasts express PlgR, being its expression greatly induced during the differentiation process. A monoclonal antibody against PIgR MAb 11G1, with cell surface-generated plasmin inhibitory abilities, was able to fully abrogate C2C12 myoblast fusion and differentiation in vitro. Moreover, both plasmin activity and PlgR expression were significantly induced in regenerating skeletal muscle in vivo, either in experimentally-injured muscle or in the dystrophic muscle of mdx mouse (an animal model of human Duchenne muscular dystrophy, DMD). The mdx muscle presents better regeneration capacities and less fibrosis than the human DMD muscle; therefore, the increase in PlgR/plasmin activity in mdx muscle suggests an important contribution of the fibrinolytic system in mdx regeneration. This study constitutes the first indication of alpha-enolase-type plasminogen receptor as an important component of skeletal myogenesis, by concentrating and enhancing plasmin generation on the cell surface.

Animals↗
PubMed2000

Effect of individual plasma lipoprotein(a) variations in vivo on its competition with plasminogen for fibrin and cell binding: An in vitro study using plasma from children with idiopathic nephrotic syndrome.

Simultaneous natural changes in lipoprotein(a) [Lp(a)] and plasminogen occur in the nephrotic syndrome and offer a unique opportunity to investigate their effects on plasminogen activation under conditions fashioned in vivo. Plasminogen, Lp(a), and apolipoprotein(a) in plasma were characterized, and their competitive binding to carboxy-terminal lysine residues of fibrin and cell membrane proteins was determined in nephrotic children during a flare-up of the disease (61 cases) and after 6 weeks (33 cases) and 6 months (42 cases) of remission. Low plasminogen concentrations (median 1.34 micromol/L, range 0.39 to 1.96 micromol/L) and high Lp(a) levels (median 0.27 g/L, range 0.07 to 2. 57 g/L) were detected at flare-up. These changes were associated with an increased Lp(a) binding ratio onto fibrin (3.13+/-0.48) and cells (1.53+/-0.24) compared with binding ratios of control children (1.31+/-0.19 and 1.05+/-0.07, respectively) with normal plasminogen and low Lp(a) (median 0.071 g/L). After 6 weeks and 6 months of remission, the values for net decrease in Lp(a) binding to fibrin were 1.7+/-0.22 (after 6 weeks) and 1.88+/-0.38 (after 6 months) and were correlated with low Lp(a) concentrations (median 0.2 g/L, range 0.07 to 0.8 g/L; and median 0.12 g/L, range 0.07 to 1.34 g/L) and inversely associated with increased plasminogen levels (median 1.82 micromol/L, range 1.4 to 2.1 micromol/L; and median 1.58 micromol/L, range 1.1 to 2.1 micromol/L). These studies provide the first quantitative evidence that binding of Lp(a) to lysine residues of fibrin and cell surfaces is directly related to circulating levels of both plasminogen and Lp(a) and that these glycoproteins may interact as competitive ligands for these biological surfaces in vivo. This mechanism may be of relevance to the atherothrombotic role of Lp(a), particularly in nephrotic patients.

Adolescent↗
PubMed2000

Plasminogen is a critical determinant of vascular remodeling in mice.

Extracellular proteolysis is likely to be a feature of vascular remodeling associated with atherosclerotic and restenotic arteries. To investigate the role of plasminogen-mediated proteolysis in remodeling, polyethylene cuffs were placed around the femoral arteries of mice with single and combined deficiencies in plasminogen and fibrinogen. Neointimal development occurred in all mice and was unaffected by genotype. Significant compensatory medial remodeling occurred in the cuffed arteries of control mice but not in plasminogen-deficient mice. Furthermore, focal areas of medial atrophy were frequently observed in plasminogen-deficient mice but not in control animals. A simultaneous deficit of fibrinogen restored the potential of the arteries of plasminogen-deficient mice to enlarge in association with neointimal development but did not eliminate the focal medial atrophy. An intense inflammatory infiltrate occurred in the adventitia of cuffed arteries, which was associated with enhanced matrix deposition. Adventitial collagen deposition was apparent after 28 days in control and fibrinogen-deficient arteries but not in plasminogen-deficient arteries, which contained persistent fibrin. These studies demonstrate that plasmin(ogen) contributes to favorable arterial remodeling and adventitial collagen deposition via a mechanism that is related to fibrinogen, presumably fibrinolysis. In addition, these studies reveal a fibrin-independent role of plasminogen in preventing medial atrophy in challenged vessels.

Animals↗
PubMed1973

The fibrinolytic pathway of human plasma. II. The generation of chemotactic activity by activation of plasminogen proactivator.

The conversion of plasminogen proactivator to plasminogen activator by Hageman factor fragments results in the generation of chemotactic activity for human neutrophils. This chemotactic activity can be distinguished from that generated by Hageman factor activation of prekallikrein and is demonstrable in plasma that is genetically deficient in prekallikrein (Fletcher factor deficiency). Both the plasminogen-activating activity and chemotactic activity produced by the interaction of Hageman factor fragments and plasminogen proactivator to yield plasminogen activator were inhibited by diisopropyl fluorophosphate (DFP) indicating an essential role for the enzymatic site in both these activities. The finding that the plasminogen proactivator tolerated a dose of DFP, which completely inactivated the plasminogen activator, reveals that the active site is protected in the precursor protein.

Blood↗
PubMed1984

Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells.

The effect of thrombin on the release of tissue plasminogen activator from endothelial cells was studied in primary cultures of human umbilical vein endothelial cells. Tissue plasminogen activator concentration in conditioned medium was measured by a two-site radioimmunometric assay. The addition of increasing concentrations (0.01 to 10 U/ml) of thrombin to confluent cultures produced a saturable, dose-dependent increase in the rate of release of tissue plasminogen activator. A sixfold increase in tissue plasminogen activator concentration (from 2 to 12 ng/ml) occurred after the addition of 1 U/ml thrombin (8 X 10(-9) M) to cultures containing 5 X 10(4) cells/cm2. Enhanced release was not observed until 6 h after thrombin addition, reached a maximum rate of 1.3 ng/ml per h between 8 and 16 h, and then declined to 0.52 ng/ml per h after 16 h. The 6-h lag period before increased tPA release was reproducible and independent of thrombin concentration. Thrombin inactivated with diisopropylfluorophosphate or hirudin did not induce an increase in tissue plasminogen activator levels. A 50-fold excess of diisopropylfluorophosphate-treated thrombin, which inhibits binding of active thrombin to endothelial cell high affinity binding sites, did not inhibit the thrombin-induced increase. It is concluded that proteolitically active thrombin causes an increase in the rate of release of tissue plasminogen activator from cultured human endothelial cells. The 6-h interval between thrombin treatment and enhanced tissue plasminogen activator release may reflect a delaying mechanism that transiently protects hemostatic plugs from the sudden increase in the local concentration of this fibrinolytic enzyme.

Blood↗
PubMed1990

Neonatal plasminogen displays altered cell surface binding and activation kinetics. Correlation with increased glycosylation of the protein.

Plasminogen isolated from 60 full-term newborns differs from adult plasminogen in carbohydrate composition, kinetic activation constants, and cell binding. Amino acid composition and amino-terminal sequence analysis data indicate that the plasminogens of neonates and adults have the same amino acid sequence. Like the adult, the neonate has two glycoforms, but both have significantly more mannose and sialic acid than the adult forms. The difference in the neonatal glycosylation is probably responsible for the altered migration observed by isoelectric focusing. Moreover, the difference in carbohydrate composition appears to be the basis of the decreased functional activity of the neonatal plasminogen. The kcat/Km ratios indicate that the overall activation rates of the two neonatal plasminogen glycoforms are lower compared with the adult glycoforms. In addition, neonatal plasminogen does not bind as well to cellular receptors compared with adult plasminogen. These studies suggest a basis for the decreased fibrinolytic activity observed in neonates.

Amino Acids↗
PubMed1993

Homocysteine-induced modulation of tissue plasminogen activator binding to its endothelial cell membrane receptor.

Endothelial cells impart thromboresistance to the blood vessel wall. As modulators of fibrinolytic activity, these cells synthesize and secrete tissue plasminogen activator (t-PA) as well as its physiologic inhibitor, plasminogen activator inhibitor-1. In addition, endothelial cells support membrane-associated assembly of plasminogen and tissue plasminogen activator. Recently, an M(r) approximately 40,000 protein expressed on endothelial cells has been shown to interact noncompetitively through disparate mechanisms with both t-PA and plasminogen, suggesting trimolecular assembly of enzyme, substrate, and receptor (Hajjar, K. A. 1991. J. Biol. Chem. 266:21962-21970). In the present study, treatment of cultured endothelial cells with DL-homocysteine was specifically associated with a selective reduction in cellular binding sites for t-PA. This 65% decrease in binding was associated with a 60% decrease in cell-associated t-PA activity. No change in affinity for t-PA or plasminogen or in the maximal number of binding sites for plasminogen was observed. Matrix-associated t-PA binding sites were not affected. These data suggest a new mechanism whereby homocysteine may perturb endothelial cell function, thus promoting a prothrombotic state at the surface of the blood vessel wall.

Carboxypeptidase B↗
PubMed2003

Plasminogen supports tumor growth through a fibrinogen-dependent mechanism linked to vascular patency.

The growth of Lewis lung carcinoma (LLC) was sustained in plasminogen-deficient mice when transplanted into the dorsal skin but was dramatically suppressed in another anatomic location, the footpad. This unanticipated negative effect of plasminogen deficiency on footpad tumor growth was entirely relieved by superimposing a deficit in fibrinogen. This finding was not simply an unusual feature of LLC tumors--T241 fibrosarcoma growth in the footpad was also restricted by plasminogen deficiency in a fibrinogen-dependent manner. The probable mechanistic basis for suppression of tumor growth was revealed through transmission electron microscopy studies of tumor tissues. Occlusive microvascular thrombi were commonplace within footpad tumors from plasminogen-deficient mice, whereas no such lesions were observed within either dorsal skin tumors from plasminogen-deficient mice or footpad tumors from mice that also lacked fibrinogen. The data infer that tumor growth in the footpad of plasminogen-deficient mice is compromised as a function of the formation and persistence of vaso-occlusive thrombi that limit tumor blood supply. These studies indicate that plasminogen and fibrinogen can serve as critical determinants of tumor growth, but their relative importance is dependent on the tumor microenvironment. Furthermore, these studies suggest that one target of plasmin(ogen) relevant to tumor progression in vivo is intravascular fibrin.

Animals↗
PubMed1993

Involvement of cyclic adenosine monophosphate-dependent protein kinase isozymes in tissue plasminogen activator secretion by rat Sertoli cells stimulated with follicle-stimulating hormone in vitro.

This study was undertaken to investigate, in freshly isolated rat Sertoli cells, the physiological function of the type I and type II cyclic adenosine monophosphate (cAMP)-dependent protein kinase isozymes in tissue-type plasminogen activator secretion and the regulation of this cAMP process by follicle-stimulating hormone (FSH). Follicle-stimulating hormone-induced tissue-type plasminogen activator secretion depends upon intracellular cAMP levels. The changes in cAMP amounts required to activate maximally the tissue-type plasminogen activator secretion are extremely small, a cAMP threshold having to be reached for triggering the tissue-type plasminogen activator output. Intact Sertoli cells were incubated with combinations of cAMP analogs specific for each cAMP-dependent protein kinase type and complementary in their cAMP binding site on the cAMP-dependent protein kinase regulatory subunits: 8-aminohexylamino-cAMP = type 1, site 1; 8-thiomethyl-cAMP = type II, site 1 and N6-benzoyl-cAMP = types I/II, site 2. This allowed us to activate selectively each cAMP-dependent protein kinase type in a synergistic manner and then to evaluate their respective influence in the specific tissue-type plasminogen activator response. We establish that both of the cAMP-dependent protein kinase types are present and functional; the activity of the type I isozyme is preponderant (60%) in the cAMP-dependent tissue-type plasminogen activator secretion. Likewise, when these cAMP analogs were coupled with endogenously generated cAMP by FSH or forskolin, both of the cAMP-dependent protein kinase types were involved in the tissue-type plasminogen activator production.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed2003

Recurrent recalcitrant gingival hyperplasia and plasminogen deficiency: a case report.

BACKGROUND: Recurrent gingival hyperplasia due to plasminogen deficiency is a rare condition due to fibrin deposition in the connective tissue. Only eight cases have previously been reported in the English literature, and all cases were diagnosed before the age of 35 years. This paper presents an older patient with recurrent gingival hyperplasia due to plasminogen deficiency (hypoplasminogenemia). METHODS: A 59-year-old woman presented with recurrent gingival swelling of 6 years' duration. Multiple biopsies performed at various time periods were histologically reported to be gingival hyperplasia with chronic inflammation. Routine hematoxylin and eosin (H & E) staining and direct immunofluorescence were performed. RESULTS: H & E-stained sections showed subepithelial, eosinophilic, amorphous, acellular deposits. Direct immunofluorescence showed positive staining for fibrin, immunoglobulin (Ig) G, IgA, and IgM. Functional plasminogen and plasminogen activator inhibitor-1 assays were done and found to be deficient. A diagnosis of gingival hyperplasia due to plasminogen deficiency (hypoplasminogenemia) was rendered. CONCLUSIONS: Recurrent gingival hyperplasia due to plasminogen deficiency (hypoplasminogenemia) is a newly recognized and rare condition. H & E staining, direct immunofluorescence, and assessment of functional plasminogen levels are essential to differentiate this condition from other conditions in which subepithelial, eosinophilic, amorphous materials are deposited.

Deficiency Diseases↗
PubMed1988

Procoagulant and plasminogen activator activities of bronchoalveolar fluid in patients with pulmonary sarcoidosis.

Tissue fibrin deposition may be an important component of inflammatory reactions. Current evidence suggests that intraalveolar procoagulant (PC) and plasminogen activator (PA) activities may be important determinants of local fibrin turnover in lung injury. In this study, we measured the PC and PA activities in cell-free bronchoalveolar lavage fluid (BALF) obtained from 17 patients with pulmonary sarcoidosis and 12 normal volunteers. Procoagulant activity was assayed by timing clot formation in a one-stage coagulation assay, and plasminogen activator activity was determined by measuring plasminogen-dependent lysis of [125I]fibrin. Mean PC activity in the sarcoidosis group was significantly elevated (102 +/- 25 versus 31.5 +/- 8.1 tissue thromboplastin units/ml; p less than 0.002), with 6 of 17 patient values beyond the 95% confidence limits of normals. These differences were not seen when PC activity was corrected for total protein in BAL. In contrast, PA activity tended to be lower in the sarcoidosis group (0.54 +/- 0.094 versus 0.643 +/- 0.106 Plough units/ml, p less than 0.3), and this difference became significant when PA was normalized to total protein (p less than 0.001). The ratio of procoagulant activity compared to plasminogen activator (PC/PA) was greater in the patients with sarcoidosis than normals (258 +/- 54 versus 40.3 +/- 6.4; p less than 0.001). The PC/PA ratios in 14 of 17 patients exceeded the 95% confidence limits of normals. In the sarcoidosis group, the PC/PA ratio correlated weakly with the number and percentage of lymphocytes retrieved by BAL. The plasminogen activator was a urokinase by molecular weight (53 kDa) and by comparing neutralization of PA activity by antibodies against urokinase and tissue plasminogen activator. The procoagulant was particulate and functioned as a factor X activator comprised of tissue thromboplastin and factor VII. We conclude that in pulmonary sarcoidosis, abnormal expression of procoagulant and plasminogen activator activities in alveolar fluid may favor accumulation of fibrin matrix at inflammatory foci.

Blood Coagulation Factors↗
PubMedDate not supplied

The urokinase-type plasminogen activator system and inflammatory joint diseases.

Much evidence indicates that the urokinase plasminogen activator (u-PA), the urokinase receptor (u-PAR) and the serpin inhibitors are critical in cell invasion processes. The balance between u-PAR-bound u-PA and inhibitors modulate a pericellular proteolytic activity able to give "stop and go" signals to invading cells. The plasminogen activation system operates both directly and in concert with the matrix-metalloproteinase system. Direct interactions of u-PAR with vitronectin and integrins further regulate cell invasion. Another line of evidence suggests that u-PA-u-PAR interaction elicits chemotaxis, chemoinvasion and cell multiplication, events that do not require plasmin generation and therefore are referred to as "plasminogen-independent". Following the description of the main molecular and functional characteristics of the cell-surface-associated plasminogen activation system, we discuss here the observations indicating a role of this system in many aspects of the rheumatic diseases, ranging from the infiltration of inflammatory cells into the affected joint, infiltration of synovial cells into the underlying cartilage, and remodeling of the cartilage itself. Evidence of the intraarticular cytokine- and growth factor-dependent regulation of the components of the plasminogen activation system are presented in terms of the paracrine and autocrine regulation of receptor-associated fibrinolysis. The roles of plasminogen-dependent and plasminogen-independent u-PAR-associated events in various phases of joint inflammation are also discussed. A knowledge of these processes is required for the therapeutic utilization of antagonists of the u-PA/u-PAR system able to control the activity of proliferating and invading cells in inflammatory joint diseases.

Arthritis, Rheumatoid↗
PubMed1999

[Lipoprotein and plasminogen serum levels in patients with diabetes mellitus type 2: risk factors for macroangiopathy? Preliminary study].

Lipoprotein(a) [Lp(a)] is the specific lipoprotein which physiological role has not been explained. Similarity between apolipoprotein(a) and plasminogen structure suggests, that Lp(a) can be the bridge connecting the lipid metabolism and the coagulation system. The aim of the study was to evaluate if there is any correlation between Lp(a) and plasminogen serum concentrations in patients with diabetes t.2. 20 males and females with diabetes t.2 in the age 19-75 years (mean: 54.9 years). The control group consisted of 15 healthy men and woman in the age of 23 years (medical students). Lp(a) was estimated by ELISA, plasminogen by turbidimetric methods. Lp(a) serum level in the examined group was: 40.06 + 59.45 mg%. In 7 patients it was over 30 mg%. In the control group: Lp(a) concentration was: 13.23 + 10.5 mg%, no one was above 30 mg%. The different was significant. Plasminogen concentration was: in patients: 94.08 + 53.08%, in the control group: 89.08 + 40.7%. There was no significant difference. Correlation index between Lp(a) and plasminogen concentrations was in the patient's group: 0.3, in the control group: 0.2. In patients with diabetes we can find increased Lp(a) commentation in serum and normal plasminogen concentration. Concentration of Lp(a) didn't demonstrate significant correlation with plasminogen serum level.

Adult↗
PubMed1999

A role of plasminogen in atherosclerosis and restenosis models in mice.

In addition to its preeminent role in fibrinolysis, the plasminogen system is believed to play a key role in mediating cell migration. Leukocyte migration into the vessel wall is a key and early event in the development of the lesions of atherosclerosis and restenosis, pathologies which may be viewed as specific examples of vascular inflammatory responses. The development of mice in which the plasminogen gene has been inactivated affords an opportunity to test the contribution of plasminogen in leukocyte migration during in vivo. This article summarizes recent studies conducted in murine models of the inflammatory response, restenosis and atherosclerosis in which leukocyte migration, and in particular monocyte/macrophage migration, has been evaluated in plasminogen-deficient mice. Recruitment of these cells through the vessel wall in inflammatory response models and into the vessel wall in restenosis and transplant atherosclerosis models is substantially blunted. These data implicate plasminogen in the migration of leukocytes in these murine models. With the numerous correlations between components and/or activation of the plasminogen system in restenosis and atherosclerosis, these results also support a role of plasminogen in the corresponding human pathologies.

Animals↗
PubMedDate not supplied

[Plasminogen binding with decapeptide and polypeptide fragments of streptokinase].

The plasminogen binding with streptokinase decapeptides, modeling the primary structure of molecule, and chymotryptic fragments of streptokinase have been investigated. The immunoenzymatic assay has shown that plasminogen binds to all streptokinase fragments with the decreasing affinity in the set of fragments: 36 > 30 > 17 > 7 > 11 kDa. Location of the binding sites in streptokinase primary structure was performed using the immobilized decapeptides on plastic pins adopted to IEA. In the presence of 10 mM 6-aminohexanoic acid 11 sites for human Glu- and mini-plasminogens, pig and bovine plasminogens binding have been found. They were of the same location for human, bovine and pig plasminogens. 3 sites were located in plasminogen alpha-domain--T43-A72, N113-T126, Q133-V158, 5 sites in beta-domain--T163-L188, A203-S222, Q239-I264, Y275-L294, T315-L340, and 3 sites in gamma-domain--T361-R362, N377-E392, T397-N410. Participation of linear part of streptokinase polypeptide chain in plasminogen--streptokinase complex formation is suggested.

Amino Acid Sequence↗
PubMed2001

Homozygous and compound-heterozygous type I plasminogen deficiency is a common cause of ligneous conjunctivitis.

Severe type I plasminogen deficiency has been recently linked to ligneous conjunctivitis, a rare and uncommon form of chronic conjunctivitis. In this study, eight unrelated ligneous conjunctivitis patients living in different parts of the world were examined. All affected subjects from which plasma was available displayed absent or markedly reduced plasminogen antigen and plasminogen functional activity. Molecular genetic studies of seven patients identified a Lys19-->Glu mutation in two boys in a homozygous state, and in two girls in a compound-heterozygous state in which the second plasminogen gene carried a missense (Arg134-->Lys) and a nonsense mutation (Cys133--> Stop), respectively. A fifth patient was shown to be homozygous for a frameshift mutation in plasminogen exon 14 (Gly565ins-G). In two unrelated subjects with ligneous conjunctivitis no mutations in the plasminogen gene were identified. Our results suggest that the Lys19-->Glu mutation is the most prevalent mutation in the plasminogen gene of patients with ligneous conjunctivitis.

Adolescent↗
PubMed2005

Differential conversion of plasminogen to angiostatin by human corneal cell populations.

PURPOSE: Maintenance of avascularity of the normal cornea and control of neovascularization during wound healing depend on a balance of angiogenic and antiangiogenic factors. The purpose of this paper is to determine the ability of corneal cells to convert plasminogen to angiostatins and to compare these products with those made by intact corneas. METHODS: RT-PCR was performed using plasminogen specific primers and the generated cDNA was sequenced. The proteins in corneal extracts, cornea conditioned medium, and medium from corneal epithelial cells, stromal fibroblasts, and myofibroblasts incubated with plasminogen were separated by SDS-PAGE and electroblotted. Western blots used monoclonal antibodies to kringles 1-3 to detect plasminogen and angiostatins. Angiostatins were isolated and tested for activity in a vascular endothelial cell proliferation inhibition assay. RESULTS: Plasminogen, its mRNA and angiostatins were found in human corneal tissue extracts from the epithelial, stromal, and endothelial layers and from cornea conditioned medium, but not in medium from cultured epithelial cells, stromal fibroblasts, or myofibroblasts. However, cultures of corneal epithelial cells and stromal fibroblasts were able to convert exogenously added plasminogen to angiostatins, whereas cultured myofibroblasts did not. Angiostatins of 38 and 34 kDa were found under all angiostatin generating conditions; however other angiostatins differed in size. Further, the angiostatins isolated from fibroblast culture supernatants inhibited vascular endothelial cell proliferation. CONCLUSIONS: Conversion of plasminogen to angiostatin is cell-type dependent. Because corneal cells generate angiostatins, use of human angiostatins may be a means of treating abnormal corneal neovascularization without the risk of side effects.

Angiostatins↗