Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since the first patient was treated with recombinant tissue plasminogen activator (t-PA) in 1984, there has been remarkable progress in our understanding of optimal methods for administration of this thrombolytic agent. As a background and foundation to clinical trials, the experimental data for bolus t-PA, adjunctive treatments and new plasminogen activators for more optimal thrombolysis are reviewed. The major findings in clinical evaluation for acute myocardial infarction to date include (1) substantial mortality reduction and improvement in cardiac function; (2) an excess of serious bleeding complications at high doses (150 mg) of t-PA; (3) rapid infarct vessel recanalization with an accelerated "front-loaded" regimen; (4) the importance of conjunctive intravenous heparin; and (5) the potential for new, combined plasminogen activator therapies. The recent data, collectively, have set the stage for a new greater than 30,000 patient mortality reduction trial entitled Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO).
Mol Biol Med 1991 Apr
PMID:Strategies for administration of tissue plasminogen activator. 180 64

Coronary thrombolysis is the treatment of choice for patients with acute Q wave myocardial infarcts who have no contraindication to such therapy. However, the time required for thrombolysis to occur and the possibility of reocclusion of the infarct-related artery following thrombolytic therapy are problems. The time required for thrombolysis to occur with currently available agents ranges from 40 to 60 minutes and the frequency of reocclusion of the infarct-related artery after tissue-type plasminogen activator is 10 to 20%. We review experimental studies and clinical evaluations in which attempts have been made to develop adjunctive therapies that when coupled with available thrombolytic interventions might shorten the time to thrombolysis and delay or prevent reocclusion. From the studies done to date, it appears that a combination of thromboxane synthesis inhibitor and receptor antagonist with a serotonin receptor antagonist and heparin shortens the time to thrombolysis and delays or prevents coronary artery reocclusion in experimental canine models with copper coil-induced coronary artery thrombi. A monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor given with tissue plasminogen activator and heparin also shortens the time to thrombolysis and delays or prevents reocclusion in experimental canine models. A mutant tissue plasminogen activator with a glycosylation defect and prolonged systemic clearance delays coronary artery reocclusion following lysis of three-hours coronary thrombi, induced by a copper coil. Thrombin inhibitors, including heparin, and synthetic inhibitors, given with tissue plasminogen activator and aspirin, appear to shorten the time to thrombolysis and delay or prevent coronary artery reocclusion in experimental canine models.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Biol Med 1991 Apr
PMID:Thrombolytic therapy: enhancement by platelet and platelet-derived mediator antagonists. 180 65

Hybrid molecules containing the catalytic domain of either tissue plasminogen activator (tPA) or single chain urokinase-type plasminogen activator (scuPA), and the fibrin binding domain of a murine antifibrin monoclonal antibody were constructed using either cDNA or genomic DNA encoding the plasminogen activator and genomic DNA encoding antifibrin monoclonal antibody 59D8. In order to optimize expression of these fusion proteins in hybridoma cells, we compared plasminogen activator 3' UT domains (which decrease mRNA stability) with immunoglobulin and beta globin 3' UT domains (which increase mRNA stability). The presence of the plasminogen activator 3' UT domain resulted in approximately tenfold lower steady-state mRNA levels, and 300 to 500-fold lower levels of expressed functional protein. The initial goal of these studies was to increase the fibrinolytic potency and selectivity of tPA or scuPA. Fusion proteins comprising an antifibrin antibody domain and the catalytic domain of either tPA or scuPA were expressed and shown to have very different properties. The fusion protein that comprised the Fab portion of an antifibrin antibody and the catalytic domain of tPA, while displaying antigen binding properties indistinguishable from those of the parent antibody and amidolytic activity similar to that of tPA, was not more efficient than tPA in an in vitro clot lysis assay. In contrast, it had been shown that tPA chemically coupled to the same antibody was four- to sixfold more efficient in fibrinolysis both in vitro and in vivo. A recombinant scuPA-antifibrin antibody hybrid, however, was sixfold more potent than scuPA in vitro and 20-fold more potent in a rabbit thrombolysis model. An explanation for this apparent discrepancy may relate to the requirement for stimulation by fibrin in order for tPA to achieve its maximal catalytic activity, a property that was demonstrated to have been lost in the antifibrin-tPA fusion protein. In contrast, the activity of urokinase is independent of the presence of fibrin. This may explain the greater success achieved in enhancing catalytic activity in the urokinase-antifibrin fusion protein. It is of additional interest that fibrin or soluble fibrin fragments stimulate the catalytic activity of both tPA and the isolated tPA B chain, demonstrating that at least part of the enhanced catalytic activity of tPA observed in the presence of fibrin is independent of fibrin binding either by the tPA kringles or finger domain (or any heavy chain domain). These data indicate that it is possible to construct recombinant hybrid molecules in which both plasminogen activator catalytic function and antibody binding are preserved.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Biol Med 1991 Apr
PMID:Hybrid molecules: insights into plasminogen activator function. 180 66

Over the last few years several groups have used retroviral vectors to achieve stable gene transfer into endothelial cells. In vitro experiments include transduction of cultured cells with genes of potential therapeutic interest, such as growth hormone and tissue plasminogen activator (t-PA). Animal studies have demonstrated the feasibility of in vivo recombinant gene expression from transduced endothelial cells, but have thus far been accomplished only with the lacZ marker gene. All studies to date have been oriented primarily toward the use of transduced endothelial cells to provide gene therapy. Numerous issues remain to be addressed with experimental data prior to the initiation of a clinical protocol using transduced endothelial cells. These issues include the introduction of larger numbers of transduced cells into the vasculature and the achievement of appropriate regulation of transgene expression. The use of retroviral vectors to study basic endothelial cell biology has been relatively ignored. The tool of retroviral vector-mediated gene transfer is available for use in answering both therapeutic and pathophysiological questions in endothelial cell biology.
Mol Biol Med 1991 Apr
PMID:Retroviral vector-mediated gene transfer into endothelial cells. 180 67

A recombinant 90-residue polypeptide fragment containing the three-loop kringle-2 domain of human tissue-type plasminogen activator (t-PA) has been studied by two-dimensional 1H-NMR spectroscopy at 500 MHz. Complete sequence-specific resonance assignments were derived. Overall, the kringle exhibits a compact, folded conformation with more than 50% of the residues in irregular structures. Elements of secondary structure were identified from sequential, medium- and long-range dipolar (Overhauser) interproton interactions. These identifications were corroborated by analysis of spin-spin scalar 3J alpha N splittings and identification of backbone amide NH protons exhibiting retarded 1H/2H exchange in 2H2O. Three antiparallel beta-sheets and six tight turns were located. In addition, one short alpha-helical region was found in the Ser43-Ala44-Gln44a-Ala44b-Leu44c-Gly45+ ++ segment; this region contains three-residue insertions unique to the t-PA and urokinase kringles. Although the secondary structure of the t-PA kringle 2 in solution is in overall agreement with that observed in the crystallographic structure of the prothrombin kringle 1 [Tulinsky, A., Park, C.H. & Skrzypczak-Jankun, E. (1988) J. Mol. Biol. 202, 885-901], the alpha-helical segment and other details of the secondary structure differ somewhat from the prothrombin homolog.
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PMID:Kringle-2 domain of the tissue-type plasminogen activator. 1H-NMR assignments and secondary structure. 190 89

The extracellular localizations of urokinase-type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), and plasminogen activator inhibitor-1 (PAI-1) were examined in cultured bovine capillary endothelial cells (BCEs) by an immunofluorescence method using BCEs treated with or without saponin and focal contact preparations. The specific immunofluorescence of cell surface uPA showed a patchy or strand-like distribution and was colocalized with vinculin strands indicating that uPA secreted from BCEs was mainly deposited at the cell surface of focal contacts. BCEs at a subconfluent density showed a higher intensity of specific immunofluorescence for uPA than when they were at a confluent density. tPA was observed over the dorsal surface of cultured BCEs and accentuated at their margins, suggesting that tPA was diffusely distributed on the luminal surface of BCEs in vivo. PAI-1 was distributed in the extracellular matrix under cultured BCEs. These findings suggest that uPA and PAI-1 are located under BCEs participating in the regulation of proteolytic activities provoked by plasminogen-PAs-plasmin system in vivo. The localization of tPA appears to be consistent with its function, which is to maintain the fluidity of the blood and to initiate thrombolysis in vivo.
Exp Mol Pathol 1991 Oct
PMID:Extracellular and cell-associated localizations of plasminogen activators and plasminogen activator inhibitor-1 in cultured endothelium. 193 10

Tissue-type plasminogen activator (tPA) is secreted by rat granulosa cells in response to treatment with activators of protein kinase A (follitropin, FSH), protein kinase C (gonadotropin-releasing hormone, GnRH) and tyrosine kinase (epidermal growth factor, EGF). Because steroid hormones have been shown to enhance the gonadotropin stimulation of ovarian differentiation, we investigated the effects of steroid hormones, alone or together with various kinase activators, on tPA activities and mRNA levels in cultured rat granulosa cells. Treatment of cells with dexamethasone (DEX; a glucocorticoid agonist) or R1881 (an androgen agonist) caused an increase in tPA secretion and mRNA levels. In addition, the stimulation of tPA activity and mRNA levels by FSH (50 ng/ml) was synergistically enhanced by cotreatment with DEX or R1881 in a time-dependent manner with 2.8- and 1.6-fold increase at 9 h after incubation as compared to cells treated with FSH alone. In contrast, treatment with diethylstilbestrol had no effect on tPA levels. Furthermore, tPA activity and mRNA levels induced by GnRH and EGF were also increased by cotreatment with DEX or R1881 as compared with cells treated with GnRH or EGF alone. Likewise, the stimulation of tPA mRNA levels by dibutyryl cAMP, a protein kinase A activator, and phorbol myristate acetate (PMA), a protein kinase C activator, was enhanced by cotreatment with DEX or R1881. These results demonstrate that glucocorticoid and androgen enhance tPA secretion and mRNA levels stimulated by FSH, GnRH and EGF in granulosa cells. The rat granulosa cells provide a useful model for studying the mechanism of regulation of tPA gene expression by steroid hormones.
Mol Cell Endocrinol 1990 Jan 22
PMID:Synergistic effect of glucocorticoids and androgens on the hormonal induction of tissue plasminogen activator activity and messenger ribonucleic acid levels in granulosa cells. 210 7

After specific chemotherapy, granulomatous fibrosis undergoes a marked reversal in liver of Schistosoma mansoni-infected mice. We have previously shown that this fibrosis reversal was related to a high proportion of the active form of the interstitial collagenase. In vitro, plasmin has been described as a physiological activator of interstitial procollagenase. Moreover, plasmin itself degrades directly matrix components such as proteoglycans and fibronectin. We have thus followed the course of the plasminogen activator, which converts plasminogen zymogen to plasmin, in liver of S. mansoni-infected mice treated with praziquantel, as schistosomicidal drug. It was found that plasminogen activator activity in the liver increases rapidly until 5 days after treatment as compared to nontreated infected mice and then diminishes gradually. Increased plasminogen activator activity appears to be one of initial events leading to this fibrosis reversal.
Cell Mol Biol 1990
PMID:Plasminogen activator activity increases during reversal of hepatic fibrosis in murine schistosomiasis. 211 35

HTC rat hepatoma cells synthesize and secrete tissue-type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1). Incubation with 8-bromo-cAMP increases tPA activity more than 50-fold and, in combination with dexamethasone, causes an additional 4-fold increase. We have investigated the mechanism of the regulation of tPA activity by cyclic nucleotides, both alone and in combination with dexamethasone, by examining the effects of these agents on tPA and PAI-1 mRNA and protein. 8-Bromo-cAMP induces only a 2-fold increase in tPA mRNA and a 5-fold increase in tPA protein which is not sufficient to account for the increase in tPA activity. However, 8-bromo-cAMP causes a 90% decrease in PAI-1 mRNA and a 60-70% decrease in PAI-1 protein, which, taken together with the modest increase in tPA mRNA and protein, can account for the increase in tPA activity. Incubation with 8-bromo-cAMP plus dexamethasone also results in an 80-90% decrease in PAI-1 mRNA, but causes a synergistic 10- to 20-fold increase in tPA mRNA and protein. Regulation of both mRNAs by 8-bromo-cAMP requires concomitant RNA synthesis. Inhibition of protein synthesis by cycloheximide totally blocks the 8-bromo-cAMP-induced decrease in PAI-1 mRNA. Cycloheximide alone causes a 5- to 10-fold increase in tPA mRNA, and no further hormonal effect is observed. Thus, 8-bromo-cAMP increases tPA activity primarily by decreasing PAI-1 mRNA accumulation.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1990 Jan
PMID:Cyclic nucleotide regulation of plasminogen activator and plasminogen activator-inhibitor messenger RNAs in rat hepatoma cells. 215 75

Messenger RNA for tissue-type plasminogen activator has been detected in RNA extracts from rat Sertoli cells in culture. Relative levels are increased in Sertoli cells stimulated by follicle-stimulating hormone or by dibutyryl cyclic AMP (dbcAMP) and decreased in cells maintained in the presence of transforming growth factor beta, type 1 (TGF-beta 1). Messenger RNA for plasminogen activator inhibitor, type 1 (PAI-1) has been detected in RNA extracts from rat peritubular myoid cells. Relative levels are increased in peritubular cells stimulated by TGF-beta 1, and decreased by the presence of dbcAMP in the medium. Data are interpreted to indicate that net protease activities in the seminiferous tubule are regulated at transcriptional levels by endocrine and paracrine agents.
Mol Cell Endocrinol 1990 Mar 26
PMID:Modulation of levels of messenger RNA for tissue-type plasminogen activator in rat Sertoli cells, and levels of messenger RNA for plasminogen activator inhibitor in testis peritubular cells. 216 Mar 84


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