Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.7 (plasmin)
 9,023 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tissue and urokinase-type plasminogen activators are serine proteases with highly restricted specificity, their best characterised role being to release the broad specificity protease plasmin from inactive plasminogen. It has frequently been suggested that these, and similar proteases, are involved in axonal growth and tissue remodelling associated with neural development. To help define what this role might be, we have studied the expression of the plasminogen activators in developing rat nervous tissue. Urokinase-type plasminogen activator mRNA is strongly expressed by many classes of neurons in peripheral and central nervous system. We have analysed its appearance in spinal cord and sensory ganglia, and found the mRNA is detectable by in situ hybridisation very early in neuronal development (by embryonic day 12.5), at a stage compatible with it playing a role in axonal or dendritic growth. Tissue plasminogen activator mRNA, on the other hand, is expressed only by cells of the floor plate in the developing nervous system, from embryonic day 10.5 and thereafter. Immunohistochemical and enzymatic analysis showed that active tissue plasminogen activator is produced by, and retained within, the floor plate. A mechanism is suggested by which high levels of tissue plasminogen activator produced by the stationary cells of the floor plate could influence the direction of growth of commissural axons as they pass through this midline structure.
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PMID:The expression of tissue and urokinase-type plasminogen activators in neural development suggests different modes of proteolytic involvement in neuronal growth. 128 56

Tissue plasminogen activator (t-PA) levels in plasma or serum were studied in 416 patients with liver diseases: acute hepatitis (AH, n = 30); fulminant hepatitis (FH, n = 36); chronic inactive hepatitis (CIH, n = 57); chronic active hepatitis (CAH, n = 39); compensated liver cirrhosis (cLC, n = 78); decompensated liver cirrhosis (dLC, n = 84); hepatocellular carcinoma (HCC, n = 64); advanced hepatocellular carcinoma (aHCC, n = 28); and compared with that of a control group (n = 106) of healthy subjects. The t-PA levels showed significant increase in patients with AH, FH, CAH, cLC, dLC and HCC, compared with normal controls. The abnormal rates in t-PA levels (higher than 8.3 ng/ml) for each type of liver diseases were 86.1% in FH, 46.2% in CAH, 50% in cLC, 85.7% in dLC, 67.2% in HCC, and 89.3% in aHCC. t-PA levels tended to be higher in more advanced liver diseases. t-PA levels significantly correlated positively with plasminogen activator inhibitor (PAI-1) in AH, cLC, dLC, HCC and aHCC, and negatively with plasmin alpha 1-plasmin inhibitor complex (PIC), plasminogen (Plg), FDP, AT III and alpha 2-plasmin inhibitor (alpha 2-PI) in dLC, prothrombin time (PT) and fibrinogen (Fbg) in HCC. t-PA levels in patients with FH, CAH and dLC were significantly higher than those in patients with AH, CIH and cLC, respectively. Moreover, the changes of t-PA levels in the clinical courses of various liver diseases revealed that t-PA levels increased sensitively with progression of liver diseases or in advanced liver diseases.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical evaluation of tissue plasminogen activator (t-PA) levels in patients with liver diseases. 131 84

Lower rates of deep vein thrombosis have been noted following total hip replacement under epidural anesthesia in patients receiving exogenous epinephrine throughout surgery. To determine whether this is due to enhanced fibrinolysis or to circulatory effects of epinephrine, 30 patients scheduled for primary total hip replacement under epidural anesthesia were randomly assigned to receive intravenous infusions of either low dose epinephrine or phenylephrine intraoperatively. All patients received lumbar epidural anesthesia with induced hypotension and were monitored with radial artery and pulmonary artery catheters. Patients receiving low dose epinephrine infusion had maintenance of heart rate and cardiac index whereas both heart rate and cardiac index declined significantly throughout surgery in patients receiving phenylephrine (p = 0.0001 and p = 0.0001, respectively). Tissue plasminogen activator (t-PA) activity increased significantly during surgery (p < 0.005) and declined below baseline postoperatively (p < 0.005) in both groups. Low dose epinephrine was not associated with any additional augmentation of fibrinolytic activity perioperatively. There were no significant differences in changes in D-Dimer, t-PA antigen, alpha 2-plasmin inhibitor-plasmin complexes or thrombin-antithrombin III complexes perioperatively between groups receiving low dose epinephrine or phenylephrine. The reduction in deep vein thrombosis rate with low dose epinephrine is more likely mediated by a circulatory mechanism than by augmentation of fibrinolysis.
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PMID:The hemodynamic and fibrinolytic response to low dose epinephrine and phenylephrine infusions during total hip replacement under epidural anesthesia. 144 77

We established that plasmin (10(-10) M to 10(-6) M) caused neutrophils (PMN) to aggregate using an in vitro assay. Plasminogen had no PMN aggregatory activity even at a concentration of 2 microM. However, plasminogen caused PMN to aggregate when incubated with plasminogen activators [tissue plasminogen activator (25-200 U/ml) or urokinase (5-500 U/ml)]. Tissue plasminogen activator and urokinase alone had no PMN aggregatory activity. Analysis of these incubation mixtures indicated that plasmin was generated in the process and that the time course of plasmin generation correlated with the aggregation response. Active-site-inhibited plasmin did not induce PMN aggregation, indicating that a functional catalytic site was required for the response. Pretreatment of PMN with either active-site-inhibited plasmin or tranexamic acid prevented PMN aggregation by plasmin, indicating that both binding of plasmin to the cell surface via the lysine binding sites and catalysis were required for the response. The generation of plasmin during activation of fibrinolysis may play a pro-inflammatory role by mediating aggregation of PMN.
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PMID:Plasmin generation induces neutrophil aggregation: dependence on the catalytic and lysine binding sites. 153 99

The changes in coagulation and fibrinolysis were studied in cases of hepatocellular carcinoma with (n = 20) and without (n = 8) transcatheter hepatic arterial embolization (TAE). The plasma levels of thrombin-antithrombin III complex (TAT) and alpha 2 plasmin inhibitor complex (PIC) were significantly elevated after TAE, concurrently with a decrease in antithrombin III and antiplasmin (alpha 2-plasmin inhibitor) levels. The elevation of TAT was most significant (2.4-fold of the pre-TAE level) on day 3, whereas that of PIC was relatively less (1.3-fold on day 3). Tissue plasminogen activator in blood was also significantly increased on day 1, but it was decreased thereafter, although plasminogen activator inhibitor (PAI) remained high for at least 7 days after TAE. In contrast, such hematological changes were not observed in patients without TAE. Thus, both coagulation and fibrinolysis were activated after TAE, but its effect on fibrinolysis was less prominent, due probably to the increased synthesis of PAI.
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PMID:Effects of transcatheter hepatic arterial embolization on coagulation and fibrinolysis in patients with hepatocellular carcinoma. 166 Feb 19

Fibronectin is a dimeric glycoprotein (Mr 440,000) involved in many adhesive processes. During blood coagulation it is bound and cross-linked to fibrin. Fibrin binding is achieved by structures (type I repeats) which are homologous to the "finger" domain of tissue plasminogen activator. Tissue plasminogen activator also binds to fibrin via the finger domain and additionally via the "kringle 2" domain. Fibrin binding of tissue plasminogen activator results in stimulation of its activity and plays a crucial role in fibrinolysis. Since fibronectin might interfere with this binding, we studied the effect of fibronectin on plasmin formation by tissue plasminogen activator. In the absence of fibrin, fibronectin had no effect on plasminogen activation. In the presence of stimulating fibrinogen fragment FCB-2, fibronectin increased the duration of the initial lag phase (= time period until maximally stimulated plasmin formation occurs) and decreased the rate of maximal plasmin formation which occurs after that lag phase mainly by increasing the Michaelis constant (Km). These effects of fibronectin were dose-dependent and were similar with single- and two-chain tissue plasminogen activator. They were also observed with plasmin-pretreated FCB-2. An apparent Ki of 43 micrograms/ml was calculated for the inhibitory effect of fibronectin when plasminogen activation by recombinant single-chain tissue plasminogen activator was studied in the presence of 91 micrograms/ml FCB-2. When a recombinant tissue plasminogen activator mutant lacking the finger domain was used in a system containing FCB-2, no effect of fibronectin was seen, indicating that the inhibitory effect of fibronectin might in fact be due to competition of fibronectin and tissue plasminogen activator for binding to fibrin(ogen) via the finger domain.
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PMID:Fibronectin decreases the stimulatory effect of fibrin and fibrinogen fragment FCB-2 on plasmin formation by tissue plasminogen activator. 182 40

Tissue plasminogen activator (t-PA) is homologous to other serine proteases and contains an apparent activation cleavage site at arginine 275. It has been demonstrated that this arginine-275 can be replaced with either glutamic acid (Tate, K. M., Higgins, D. L., Holmes, W. E., Winkler, M. E., Heyneker, H. L., and Vehar, G. A. Biochemistry 26, 338-343, 1987) or glycine (Peterson, L. C., Johannessen, M., Foster, D., Kumar, A., and Mulvihill, E. Biochim. Biophys. Acta 952, 245-254, 1988; Boose, J. A., Kuismanen, E., Gerard, R., Sambrook, J. and Gething, M.-J. Biochemistry 28, 635-643, 1989) so that the product of the plasminogen activation reaction, plasmin, can no longer hydrolyze the one-chain form of t-PA to the two-chain form. These "one-chain" t-PA variants had diminished activity, compared to wild-type t-PA, in the absence of a cofactor, but in the presence of the fibrin(ogen) cofactor the two variants had activity similar to wild-type t-PA. In order to compare the effects of all possible substitutions, t-PA variants with each of the other nineteen amino acids besides arginine at position 275 were produced by site-directed mutagenesis. All were recovered from cell culture supernatants completely in the one-chain form, except for R275 (wild-type) and R275K, which were partially converted to the two-chain form. These latter two species could be completely converted to the two-chain form by plasmin. In addition, these two forms showed significantly more plasminogen activating activity in the absence of a fibrin(ogen) cofactor, compared to the other 18 variants. In the presence of a cofactor, all of the t-PA mutants had plasminogen activating activity equivalent to wild-type t-PA, except for R275C. The R275C t-PA had comparatively less clot lysis and fibrin binding activity as well. Presumably the new cysteine in this variant was involved in a mixed disulfide or caused misfolding of the molecule resulting in decreased activity. The difference in the plasminogen activating activity of one- and two-chain forms of t-PA was investigated by determining the apparent Michaelis constants and the apparent turnover numbers for R275E t-PA, which remains in the one-chain form throughout the assay, and two-chain R275 t-PA. The kinetic constants were measured in both the presence and the absence of plasmin-digested fibrinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The effect of the one-chain to two-chain conversion in tissue plasminogen activator: characterization of mutations at position 275. 213 48

The production of interleukin (IL 1) by normal human peripheral blood monocytes purified by Ficoll-Hypaque density sedimentation, Percoll-gradient sedimentation, and plastic adherence can be detected as early as 30 min intracellularly, and extracellularly within 1 hr after stimulation with lipopolysaccharide (LPS). Production of mRNA coding for the isoelectric point 7.0 species of IL 1 was also detected as early as 1 hr after LPS stimulation and reached a maximum level at 6 hr. Cell-associated IL 1 activity could be extracted with CHAPS detergent from every cell fraction (i.e., membranes, cytosol, and particulates), but was present mainly (greater than 95%) in the cytosol of LPS-activated monocytes and the myelomonocytic cell line, THP-1. The apparent m.w. of IL 1 activity on high pressure liquid chromatography gel filtration in every cell fraction was approximately 23,000 daltons, with a minor peak at 31,000 daltons, whereas the IL 1 activity in the culture supernatants was 17,000 daltons. Western blotting analysis of LPS-stimulated monocyte extracts showed two forms of IL 1 corresponding to 31,000 daltons and 25,000 daltons. Exposure of viable cells to trypsin and plasmin released biologically active 23,000 dalton IL 1 only from IL 1-producing cells such as activated monocytes and IL 1-producing Ebstein-Barr virus B lymphocyte cell lines. Consequently, biologically active IL 1 is presumably exposed on the outer surface of cell membranes. Furthermore, IL 1 release by human monocytes in plasminogen-depleted fetal calf serum was considerably decreased. Conversely, supplementation of plasminogen-depleted serum with purified plasminogen restored the IL 1 production, suggesting that plasmin or plasmin-like factors may be involved in the regulation of the release of IL 1 from IL 1-producing cells. In conclusion, the results suggest that IL 1 is rapidly produced, is pooled in the cytosol, and in part is processed by enzymes, is transferred to the plasma membranes, and is then released from the cells. Tissue plasminogen activator and serum enzymes such as plasmin may therefore be involved in the release of IL 1 from IL 1-producing cells.
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PMID:Intracellular localization of human monocyte associated interleukin 1 (IL 1) activity and release of biologically active IL 1 from monocytes by trypsin and plasmin. 242 Aug 74

The interaction of tissue plasminogen activator derived from a melanoma cell line with a specific plasminogen activator inhibitor from placental tissue, which inhibits urokinase and tissue plasminogen activator but not plasmin, was studied. Tissue plasminogen activator exists in two forms, a one chain and a two chain molecule. It was found that the two enzyme species each form 1:1 complexes with the inhibitor and that the two chain enzyme binds the inhibitor very strongly, Ki = 3 X 10(-10) mol/l, whereas the one chain enzyme forms a much weaker complex, Ki is approximately 10(-7) to 10(-8) mol/l. Substrate hydrolysis is much more efficiently catalysed by the two chain plasminogen activator than by the one chain activator.
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PMID:Different inhibition of one and two chain tissue plasminogen activator by a placental inhibitor studied with two tripeptide-p-nitroanilide substrates. 293 Aug 96

Tissue plasminogen activator (TPA) converts plasminogen to plasmin within the fibrin clot, thus localizing activation of fibrinolysis. To determine the extent to which platelets promote activation of plasminogen by TPA, we studied the interaction of TPA and plasminogen with unstimulated platelets. Normal washed platelets incubated in the presence of physiologic concentrations of plasminogen (180 micrograms/mL) and TPA (20 ng/mL) failed to generate plasmin activity. In contrast, incubation of platelets with TPA concentrations achieved during thrombolytic therapy (40 to 800 ng/mL) produced a tenfold to 50-fold increase in plasmin activity. After exposure to plasminogen and 200 ng/mL of TPA for one hour, platelets failed to agglutinate in the presence of ristocetin. Incubation of platelets suspended in autologous plasma with 400 ng/mL of TPA for one hour also inhibited ristocetin-induced agglutination. Exposure of platelets to plasminogen and increasing concentrations of TPA correlated with a decrease in glycoprotein Ib (GPIb) and an increase in glycocalicin, as shown by immunoblotting. The glycoprotein IIb/IIIa (GPIIb/IIIa) complex and a 250,000-dalton protein also disappeared from washed platelets after incubation with plasminogen and 200 ng/mL of TPA for one hour. These platelets failed to aggregate in the presence of adenosine diphosphate (ADP) or gamma thrombin, although aggregation in response to calcium ionophore A23187 and arachidonic acid remained intact. However, aggregation in response to all four agonists was normal when platelets were incubated with TPA in the presence of autologous plasma. Platelets from a patient with Glanzmann's thrombasthenia also generated plasmin in the presence of TPA. Hydrolysis of GPIb and inhibition of ristocetin-induced agglutination occurred to a lesser extent with these platelets than with control platelets. We conclude that platelets provide a surface for activation of plasminogen by pharmacologic amounts of TPA. Plasmin generation leads to degradation of GPIb and decreased ristocetin-induced agglutination in normal and thrombasthenic platelets, as well as degradation of GPIIb/IIIa in normal washed platelets and inhibition of ADP and gamma thrombin-induced aggregation. These findings suggest that pharmacologic concentrations of TPA may cause platelet dysfunction due to plasmin generation on the platelet surface.
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PMID:Activation of plasminogen by tissue plasminogen activator on normal and thrombasthenic platelets: effects on surface proteins and platelet aggregation. 294 Oct 84


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