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

The urokinase-type plasminogen activator receptor (u-PAR) was demonstrated on cultured smooth muscle cells (SMCs) of bovine aorta. Binding of 125I-urokinase-type plasminogen activator (u-PA) was concentration dependent and saturable within 45-60 minutes. A similar concentration and time dependence was found in functional plasminogen activation studies. Human two-chain high-molecular-weight u-PA and its proenzyme (pro-u-PA) bound specifically with identical affinity (Kd). Activation of pro-u-PA was strongly accelerated on binding to SMCs and occurred only in the presence of plasminogen on the cell surface. A 100-fold molar excess of unlabeled high-molecular-weight u-PA effectively blocked binding of the radiolabeled ligands; tissue-type plasminogen activator, plasminogen, low-molecular-weight u-PA, and unrelated proteins did not. 125I-u-PA binding was abolished by a monoclonal antibody against the specific u-PA sequence responsible for u-PAR binding. Binding of u-PA sharply decreased on SMC exposure to phosphatidylinositol-specific phospholipase C, confirming the glycan phospholipid cell anchorage of u-PAR. Bovine and human alpha-thrombin (240 nM) increased the binding of 125I-u-PA fivefold, translating into an increase in the number of sites per cell from about 10(5) to 5 x 10(5) without significant change in the Kd (1.29 +/- 0.39 nM). Active site blockade of thrombin by D-Phe-Pro-Arg-chloromethyl ketone resulted in the total loss of stimulatory activity, as did the use of the inactive active site thrombin mutant, S205A. Hirugen (100 microM), which blocks the anion-binding exosite of thrombin, blocked u-PAR stimulating activity. Thus, both the catalytic activity and integrity of the exosite are important for thrombin's stimulatory activity. Other SMC mitogens (epidermal growth factor, transforming growth factor-beta 1, basic fibroblast growth factor, platelet-derived growth factor, and phorbol 12-myristate 13-acetate) increased u-PAR expression on SMCs six- to 20-fold while concomitantly increasing Kd four- to 10-fold. In all cases the induction of u-PAR was dependent on de novo protein synthesis. These observations assign a possible role for thrombin and other mitogens in u-PAR regulation, thereby influencing the pericellular proteolysis that is important in SMC migration and atheromatous plaque development.
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PMID:Regulation of the urokinase-type plasminogen activator receptor on vascular smooth muscle cells is under the control of thrombin and other mitogens. 132 97

Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.
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PMID:On the role of coagulation and fibrinolysis in atherosclerosis. 134 93

Decreased fibrinolytic capacity has been suggested to accelerate the process of arterial atherogenesis by facilitating thrombosis and fibrin deposition within developing atherosclerotic lesions. Type 1 plasminogen activator inhibitor (PAI-1) is the primary inhibitor of tissue-type plasminogen activator and has been found to be increased in a number of clinical conditions generally defined as prothrombotic. To investigate the potential role of this inhibitor in atherosclerosis, we examined the expression of PAI-1 mRNA in segments of 11 severely diseased and 5 relatively normal human arteries obtained from 16 different patients undergoing reconstructive surgery for aortic occlusive or aneurysmal disease. Densitometric scanning of RNA (Northern) blot autoradiograms revealed significantly increased levels of PAI-1 mRNA in severely atherosclerotic vessels (mean densitometric value, 1.7 +/- 0.28 SEM) compared with normal or mildly affected arteries (mean densitometric value, 0.63 +/- 0.09 SEM; P less than 0.05). In most instances, the level of PAI-1 mRNA was correlated with the degree of atherosclerosis. Analysis of adjacent tissue sections from the same patients by in situ hybridization demonstrated an abundance of PAI-1 mRNA-positive cells within the thickened intima of atherosclerotic arteries, mainly around the base of the plaque. PAI-1 mRNA could also be detected in cells scattered within the necrotic material and in endothelial cells of adventitial vessels. In contrast to these results, PAI-1 mRNA was visualized primarily within luminal endothelial cells of normal-appearing aortic tissue. Our data provide initial evidence for the increased expression of PAI-1 mRNA in severely atherosclerotic human arteries and suggest a role for PAI-1 in the progression of human atherosclerotic disease.
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PMID:Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. 149 92

Based on apparent higher recanalization rates of the infarct-related artery, preferential use of thrombolytic agents with high clot specificity has been proposed for treating patients with acute myocardial infarction. In the Thrombolysis in Myocardial infarction (TIMI-I) and European Cooperative Group studies, higher reperfusion rates were observed with alteplase compared with streptokinase, causing many to assume that the former would achieve a greater reduction in early hospital mortality. However, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI-2) and its associated International Study Group failed to show any differences in 15-day mortality between these agents in more than 20,000 patients. This apparent lack of correlation between reperfusion rates and early mortality may be explained in part when one considers that recanalization or patency rates measured at a given point in time, such as 90 minutes after onset of therapy, fail to define the subsequent vessel status. Early reocclusion is the major reason for this and is a major limitation to the clinical efficacy of thrombolytic drugs. Following recanalization, residual fibrin-bound thrombin adherent to the site of arterial injury from plaque rupture strongly promotes rethrombosis. Although antiplatelet and antithrombin agents such as aspirin and heparin help to decrease rethrombosis, these agents are far from ideal. Thrombolytic agents that produce a significantly prolonged systemic thrombolytic state, such as streptokinase and anistreplase, are likely to result in less rethrombosis. Therefore, a systemic fibrinolytic state would appear to be an advantage rather than a disadvantage, particularly because the incidence of intracerebral hemorrhage does not appear to be greater with their use compared with agents producing less systemic fibrinolysis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Thrombolysis, anticoagulation, and reocclusion. 174 47

Ample evidence exists to support the major role of intracoronary thrombosis superimposed on a disrupted plaque in unstable angina. Consequently, thrombolytic treatment, already established to be highly beneficial in patients with acute myocardial infarction, might also be indicated in patients with unstable angina. The clinical response to thrombolytic treatment has been evaluated in several small-sized studies with inconsistent and somewhat deceiving results. Thus, the role of thrombolysis in the treatment of unstable angina is still controversial. Two ongoing large-scale, randomized, controlled trials, the Third Thrombolysis in Myocardial Infarction (TIMI III) in the United States testing recombinant tissue-type plasminogen activator and UNASEM in Europe testing anisoylated plasminogen-streptokinase activator complex will, it is hoped, solve the debate. At present, early thrombolysis might be considered for the treatment of the subset of patients with severe rest angina associated with transient ST-T ischemic changes.
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PMID:Thrombolysis in unstable angina: results of clinical studies. 189 74

The digoxigenin-based non-radioactive DNA labeling and detection system was applied in various hybridization protocols using digoxigenin-labeled probes obtained by enzymatic incorporation of Dig-[11]-dUTP. In genomic blots single-copy genes (human tissue-type plasminogen activator, constant part of immunoglobulin kappa light chain) can be detected with only 0.5 to 5 micrograms human DNA depending on the type of probe and the length of the hybridizing region. Due to its high sensitivity and specificity, the digoxigenin system is also appropriate for colony-, plaque-, and in situ hybridizations with metaphase chromosome spreads and fixed cells. Especially in the latter applications it is of great advantage, that with the digoxigenin system any significant background or unspecific side reactions with biological materials are avoided.
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PMID:Non-radioactive labeling and detection of nucleic acids. III. Applications of the digoxigenin system. 196 85

The hearts of 61 patients (39 men aged 64 +/- 11 years) who died from 5 hours to 42 days (median 3 days) after a fatal first acute myocardial infarction without having undergone percutaneous transluminal coronary angioplasty or coronary bypass surgery were studied to compare clinical and cardiac morphologic features of patients receiving thrombolytic therapy with tissue-plasminogen activator (t-PA) to those not receiving thrombolytic therapy. Comparison of findings in the 23 patients who received t-PA intravenously 3 +/- 1 hours after onset of symptoms, with the 38 patients who did not, showed similar baseline characteristics with respect to: age, gender, history of hypertension; location of the infarct; heart weight; severity and numbers of coronary arteries narrowed; and frequencies of plaque rupture, plaque hemorrhage and coronary thrombi. Among the patients receiving t-PA, however, there was a greater frequency of platelet-rich (fibrin-poor) thrombi in the infarct-related coronary arteries (6 of 11 vs 4 of 25 thrombi; p = 0.02), more nonocclusive than occlusive thrombi (6 of 11 vs 4 of 25 thrombi; p = 0.02), and a lower frequency of myocardial rupture (left ventricular free wall or ventricular septum) (5 of 23 [22%] vs 18 of 38 [46%]; p = 0.045).
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PMID:Comparison of coronary and myocardial morphologic findings in patients with and without thrombolytic therapy during fatal first acute myocardial infarction. The TIMI Investigators. 212 Oct 15

Extravascular participation of the serine protease plasminogen activator (PA) in tissue remodelling and cell migration may be relevant in the regulation of periodontal homeostasis and the pathogenesis of periodontal disease. The molecular nature of authentic PA in crevicular fluid has been characterized, and this study has sought to determine whether human supragingival plaque also contains PA; if so, of which molecular species and from what source. Thirty samples of supragingival plaque plaque from 10 individuals, extensively washed to remove adherent saliva, were all found by substrate analysis to have tissue-type PA (tPA) activity. Unstimulated parotid or mixed saliva also showed tPA activity, but submandibular saliva had no measurable PA activity. Freshly isolated plaque microbes cultured under aerobic or anaerobic conditions contained no PA activity (preliminary investigation). PA activity was restricted to individual epithelial cells suggesting that the origin of PA activity in human supragingival plaque is in part from plaque-adherent epithelial cells.
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PMID:Molecular characterization of plasminogen activator in human supragingival plaque. 250 47

Most acute myocardial infarctions are associated with thrombotic occlusion superimposed on a significant coronary arterial atherosclerotic plaque. Restoration of coronary flow can limit ultimate infarct size if accomplished within 4 to 6 hours of the onset of symptoms. Thrombolytic therapy with intracoronary and intravenous streptokinase or by tissue-specific plasminogen activator is effective as a rapid means of reperfusing infarcting myocardium. Percutaneous coronary angioplasty and surgically constructed bypass grafts can convert a tenuous source of coronary flow to reliable, unrestricted myocardial perfusion. Although acute surgical revascularization can be performed during an evolving infarction, the time restraints imposed by ischemic cellular injury dictate that bypass grafting serve as an adjunct to thrombolytic therapy as a means of preventing rethrombosis and providing global as well as regional revascularization. The vast potential benefit for minimizing morbidity and mortality resulting from quantitative limitation of acute myocardial necrosis mandates scientific evaluation of the new armamentarium directed at medical-surgical reperfusion.
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PMID:The surgeon's role in the treatment of acute myocardial infarction. 293 Sep 8


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