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)

Psoriatic scale proteases were found to be extracted effectively in salt solution (1 mol/l) containing Triton X-100 (5 g/l). The extraction in dilute buffer or sucrose yielded low activities. The acid (0.25 N H2SO4) and KSCN (2 mol/l) solutions effectively extracted plasminogen activator. Fibrinolysin was most active in salt (1 mol/l KCl) and in KSCN (2 mol/l) extracts. Psoriatic scale proteases were fractionated by Sephadex G-100 gel filtration and further by DEAE cellulose chromatography. Five different enzyme preparations were obtained. The first preparation, resembling cathepsin D, effectively hydrolysed hemoglobin at pH 3.5 and casein at pH 5.8 and was insensitive to protease modifiers. The second preparation effectively hydrolysed trypsin substrates (AGLME, TAME, BAEE and BANA) and also histone and casein at pH 7.2 and was inhibited by protease inhibitors, TLCK and E-600. The third preparation hydrolysed histone and casein at pH 10.2 and was effectively inhibited by E-600 and partially by protease inhibitors and TPCK. The fourth preparation, resembling cathepsin B1, hydrolysed BANA and BAEE at pH 5.8 and was activated by SH-reagents and EDTA. The fifth enzyme preparation hydrolysed ATEE and was inhibited by E-600 and TPCK. Plasminogen activator was found mainly in the second enzyme preparation and fibrinolysin activity in the third and fifth enzyme preparations. The second, third and fifth enzyme preparations were different from the enzymes found in healthy human skin. The proteases of psoriatic scale resemble those of tissue and cell cultures undergoing rapid cell division. The possible role of proteases in the increased cell division in psoriasis plaque is discussed.
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PMID:Human skin proteases. Fractionation of psoriasis scale proteases and separation of a plasminogen activator and a histone hydrolysing protease. 0 31

To elucidate the mechanism of synovial damage in rheumatoid arthritis, we studied the activation of latent collagenases released from adherent rheumatoid synovial cells in culture. Latent enzyme was not complexed with alpha2 macroglobulin, the prinicpal proteinase inhibitor in serum, and could be activated by trypsin in the presence of alpha2 macroglobulin if sufficient proteinase was added to saturate inhibitor. Latent collagenase bound half as effectively to collagen fibrils as active enzyme. Plasmin was a threefold better activator of latent enzyme than trypsin and could be generated by addition of plasminogen to synovial-cell cultures. Production of both collagenase and plasminogen activator was inhibited by dexamethasone (10(-9) M). These studies emphasize in importance of control of activation in regulation collagenase activity, It is likely that rheumatoid synovium produces both latent collagenase and plasminogen activator; plasmin is activated from its zymogen, plasminogen, present in inflamed tissues, and in turn activates collagenase.
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PMID:Endogenous activation of latent collagenase by rheumatoid synovial cells. Evidence for a role of plasminogen activator. 6 27

The major plasmin inhibitors namely alpha2-plasmin inhibitor and alpha2-macroglobulin were compared for their effects on lysis of fibrin clot. Plasmin fibrinolytic activity was immediately inhibited by alpha2-plasmin inhibitor, whereas alpha2-macroglobulin inhibited plasmin progressively. Urokinase(plasminogen activator)-induced clot lysis was inhibited efficiently by alpha2-plasmin inhibitor present in the clot. Inhibition of urokinase-induced clot lysis by alpha2-macroglobulin was weak and the molar concentration necessary for alpha2-macroglobulin to achieve the same degree of inhibition as that achieved with alpha2-plasmin inhibitor was about 10 times higher than that of alpha2-plasmin inhibitor. Binding of Lys-plasminogen to fibrin was inhibited by alpha2-plasmin inhibitor but not by alpha2-macroglobulin. Molar concentrations of alpha2-plasmin inhibitor which were effective in inhibiting the binding were 30 times less than that of 6-aminohexanoicacid. alpha2-Plasmin inhibitor was found to interact with Lys-plasminogen to form a weakly-bound complex which is dissociable in the presence of 6-aminohexanoic acid, suggesting that inhibition of binding of Lys-plasminogen to fibrin by alpha2-plasmin inhibitor may be due to interaction of alpha2-plasmin inhibitor with a specific site of the plasminogen molecule and that the site may be 6-aminohexanoic acid-binding site. It is suggested that alpha2-plasmin inhibitor is more reactive and efficient inhibitor of fibrinolysis than alpha 2-macroglobulin.
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PMID:Effects of alpha2-plasmin inhibitor on fibrin clot lysis. Its comparison with alpha2-macroglobulin. 7 50

Fibrinogen was depleted in dogs injected with a single dose of bothropase even if pretreatment followed by a continuous infusion of antifibrinolytic drugs was performed during defibrination. The activation of the fibrinolytic system as a secondary effect of the defibrination syndrome induced by bothropase injection was blocked completely by aprotinin (Trasylol) but not by EACA. Plasmin activity in spite of the inhibition of plasminogen activator suggests that, either an excess of activator is released in circulation or a plasmin-antiplasmin complex is dissociated by the circulating fibrin, according to the hypothesis of Ambrus and Markus [1], and Back et al. [4] for the mechanism of fibrinolysis in vivo. An experimental model is suggested for the study of the fibrinolytic mechanism in vivo, by the association of defibrinating agents, antivenom and antifibrinolytic drugs.
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PMID:Experimental defibrination and bothropase: a study on the fibrinolytic mechanism in vivo. 14 12

Plasmin inhibition by alpha 2-antiplasmin (alpha 2AP) is regulated by the vascular components fibrin(ogen) fragments, plasminogen and lipoprotein (a). Kinetic analysis demonstrates that CNBr-derived fibrinogen fragments completely protect plasmin from alpha 2AP. Plasminogen and 6-aminohexanoic acid decrease the rate of inhibition by 5- and 10-fold respectively. These studies show that CNBr-derived fibrinogen fragments and 6-aminohexanoic acid bind plasmin kringle(s) with binding constants of 2 micrograms/ml and 120 microM respectively, and that plasminogen binds to alpha 2AP with an affinity of 0.5 nM. The unmodulated inhibition is not effected by the presence of lipoprotein (a), but in the presence of protective CNBr-derived fibrinogen fragments the rate of inhibition is increased by the presence of the lipoprotein. The kinetics demonstrate that lipoprotein (a) binds to CNBr-derived fibrinogen fragments with an affinity of 4 nM, displacing plasmin from the protective surface. In addition, tissue-type plasminogen activator and trypsin inhibition by alpha 2AP is not slowed by the presence of CNBr-derived fibrinogen fragments or plasminogen (Pg), respectively. These kinetics suggest that the initial reversible interaction between plasmin and alpha 2AP is mediated by binding of the inhibitor to the kringle 1 domain of plasmin, with a reversible inhibition constant (Ki) of 5.0 x 10(-10) M. Under conditions where this kringle-inhibitor interaction is blocked, the reversible inhibition still occurs between the plasmin and alpha 2AP, but the initial Ki is increased to 5.0 x 10(-9) M. These data suggest that, in the circulation, plasmin inhibition by alpha 2AP may be down-regulated by fibrin, fibrin(ogen) fragments and Pg, but up-regulated by lipoprotein (a) in the presence of fibrin or fibrin(ogen) fragments. The lipoprotein (a)-mediated promotion of plasmin inhibition may provide an additional mechanism by which the lipoprotein impairs fibrinolysis and promotes atherosclerosis.
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PMID:Lipoprotein (a) promotes plasmin inhibition by alpha 2-antiplasmin. 138 85

Plasmin inhibited the biosynthesis of tissue-type plasminogen activator (tPA) antigen by human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner. The amount of tPA antigen found in the 24-h conditioned medium of cells treated with 100 nM plasmin for 1 h was 20-30% of that in the control group. However, in contrast to tPA, such treatment led to a 3-fold increase in plasminogen activator inhibitor (PAI) activity, whereas the amount of PAI type 1 antigen was unchanged. The effects of plasmin on HUVEC were binding- and catalytic activity-dependent and were specifically blocked by epsilon-aminocaproic acid. Microplasmin, which has no kringle domains, was less effective in reducing tPA antigen biosynthesis or enhancing PAI activity in HUVEC. Kringle domains of plasmin affected neither tPA antigen nor PAI activity of the cells. Other proteases including chymotrypsin, trypsin, and collagenase at comparable concentrations did not have a significant effect on the biosynthesis of tPA antigen or PAI activity of HUVEC. Thrombin stimulated the biosynthesis of tPA and PAI-1 antigens by HUVEC. Thrombin also stimulated an increase in the protein kinase activity in HUVEC, whereas plasmin inhibited the protein kinase activity of the cells. It is possible that plasmin regulates the biosynthesis of tPA in HUVEC through the signal transduction pathway involving protein kinase.
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PMID:Plasmin and the regulation of tissue-type plasminogen activator biosynthesis in human endothelial cells. 138 68

The generation of the proteolytic enzyme plasmin from its inactive precursor plasminogen, mediated by so called plasminogen activators, is the essential step in thrombolytic therapy. Plasmin is responsible for the degradation of the insoluble fibrin, the major component of a thrombus, to soluble fibrin degradation products. So far, the use of the more recently developed thrombolytic agents single-chain urokinase-type plasminogen activator (scu-PA) and tissue-type plasminogen activator (t-PA) were disappointing, mainly due to some of their negative properties in vivo, i.e., rapid inhibition and/or hepatic clearance. Besides some background information on the haemostatic balance; t-PA and scu-PA structure; and mechanisms of action, we here review some reported attempts to improve on these agents for thrombolytic therapy following various strategies. One of the more potential strategies, antibody-targeted thrombolytic therapy using bispecific monoclonal antibodies, is discussed somewhat more extensively, as are the several procedures that can be followed for bispecific antibody preparation.
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PMID:The potential improvement of thrombolytic therapy by targeting with bispecific monoclonal antibodies: why they are used and how they are made. 141 66

TGF-beta plays a pivotal role in the pathological accumulation of extracellular matrix in experimental glomerulonephritis. Increased TGF-beta expression leads to increased synthesis and deposition of extracellular matrix components while administration of anti-serum to TGF-beta suppresses the major manifestations of the disease. We hypothesized that TGF-beta might also enhance matrix accumulation by decreasing matrix turnover via effects on protease/protease inhibitor balance. Plasmin is a potent protease capable of degrading a variety of matrix molecules. Plasmin generation from plasminogen is regulated by plasminogen activator(s) (PA) and plasminogen activator inhibitor(s) (PAI). In this study PA activity was markedly reduced and PAI-1 synthesis dramatically increased when TGF-beta was added to normal glomeruli. Diseased glomeruli also showed decreased PA activity, increased PAI-1 synthesis and increased PAI-1 deposition into matrix. Administration of anti-TGF-beta serum to glomerulonephritic rats blocked the expected increase in glomerular PAI-1 deposition. Thus changes in the PA/PAI balance favoring accumulation of matrix are induced by TGF-beta in normal glomeruli and are present in nephritic glomeruli when endogenous TGF-beta production is high. Our findings implicate the plasmin protease system in tissue repair following acute glomerular injury and suggest another mechanism by which TGF-beta enhances the matrix accumulation characteristic of many glomerular diseases.
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PMID:Glomerular matrix accumulation is linked to inhibition of the plasmin protease system. 147 81

The success of plasminogen activators in recanalizing occluded coronary arteries may be influenced by their effect on blood platelets; however, some previous studies have shown platelet activation by plasmin and thrombolytic agents while others have shown an inhibitory effect. Moreover, it has not been determined whether these effects reflect an alteration of intracellular signal transduction, fibrinogenolysis, degradation of adhesive protein receptors, or a combination of these events. To distinguish among these possibilities, the increase of cytoplasmic [Ca2+] [( Ca2+]i), which is an intracellular marker of platelet activation that precedes fibrinogen binding to the surface of activated platelets, was measured along with aggregation and release of 5-hydroxytryptamine (5-HT) in washed human platelets incubated with plasmin or recombinant tissue-type plasminogen activator (rt-PA). Plasmin (0.1 to 1.0 CU/mL) induced a prompt, concentration-dependent [Ca2+]i increase when added to platelets, but subsequently inhibited the [Ca2+]i increase in response to thrombin or the endoperoxide analog U44069. Platelet aggregation accompanied the [Ca2+]i increase if the platelets were stirred, while the aggregation of platelets unstirred during plasmin incubation was inhibited upon agonist addition and resumption of stirring. The release of 5-HT paralleled the [Ca2+]i increase induced by plasmin and was also inhibited after the subsequent addition of a second agonist. The effects of rt-PA, added with plasminogen (100 micrograms/mL), were similar to those of plasmin, and could be accounted for by the concentration of plasmin generated. The ADP scavengers apyrase and CP/CK each prevented the [Ca2+]i increase, and aggregation caused by plasmin or rt-PA, and also prevented their inhibitory effects on thrombin-induced activation. Thus, plasmin and rt-PA initially activate platelets, inducing a [Ca2+]i increase, and, if the platelets are stirred, aggregation. Such activation is followed by subsequent inhibition of cellular activation by a second agonist; the inhibitory effect is in proportion to the degree of initial activation, and ADP is an important cofactor in both processes. These platelet effects occur at rt-PA concentrations achievable clinically, and may affect the success of therapy with thrombolytic and adjunctive agents.
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PMID:Platelet activation and subsequent inhibition by plasmin and recombinant tissue-type plasminogen activator. 153 Aug 14

Osteoblasts produce proteolytic enzymes and their production is regulated by osteotropic agents. It has been suggested that these proteases play a role in bone resorption by removing the superficial collagenous layer from the bone matrix and indirectly inducing migration of osteoclast precursors towards the bone matrix. We examined the effect of the plasminogen activator tPA on osteoclastic resorption using 17-day-old mouse embryonic long bone explants representing different stages of osteoclast development, that is, radii containing already mature osteoclasts and metacarpals containing no mature osteoclasts but only osteoclast precursors/progenitors which are still confined to the periosteum. Tissue type PA stimulated osteoclastic resorption (measured as 45Ca-release) in 17-day-old fetal metacarpals but not in radii of the same animal. Blocking the enzymatic activity of tPA did not inhibit its effect on osteoclastic resorption. Plasmin, the direct product of PA enzymatic activity, did not induce osteoclastic resorption. However, a tPA-mutant missing the growth-factor-like domain of the molecule, failed to stimulate 45Ca-release from the metacarpals. In addition, in both systems tPA and transforming growth factor alpha had similar effects on osteoclastic resorption. The finding that tPA stimulated 45Ca-release only in the metacarpals suggests that tPA has an effect on osteoclast formation rather than on the activity of already mature osteoclasts. Under the experimental conditions used this effect seems to be mediated by the growth factor domain of tPA rather than by the enzymatic activity of the molecule.
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PMID:The effect of tissue type plasminogen activator (tPA) on osteoclastic resorption in embryonic mouse long bone explants: a possible role for the growth factor domain of tPA. 153 5


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