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)

Plasminogen activators and inhibitors may be important early in primate implantation but evidence for this is sparse in non-human primates. We define the expression of urokinase type plasminogen activator (uPA), tissue-type plasminogen activator (tPA), plasminogen activator inhibitor type 1 (PAI-1) and type 2 (PAI-2), the receptor for uPA (uPAR) and fibrin/fibrinogen in monkey implantation sites. In situ hybridization and immuno-histochemical localization of rhesus monkey implantation sites (day 15-16 postovulation) indicate: (1) uPA mRNA is localized to placental trophoblast, epithelial plaque and endometrial stroma. (2) tPA mRNA is mainly expressed in glandular cells of endometrium. (3) PAI-1 expression is linked to a specific population of trophoblasts that confront maternal cells, adding support to our view that it has a regulatory role in trophoblast invasion. (4) Localization of tPA antigen confirms that uterine glands are the major source of tPA and that it is also closely associated with fibrin(ogen) suggesting its possible function during implantation is fibrinolysis. (5) Unlike uPA mRNA, however, the distribution of uPA protein and its cell surface receptor uPAR suggests that it mediates trophoblast invasion and plays a significant role in angiogenesis. (6) PAI-2, the inhibitor associated with pregnancy in humans, was found in unidentified cells located specifically along the maternofetal junction. This localization adjacent to areas of cell death at the maternofetal junction implies that it may have a role as a protective curtain with anti-apoptotic function. In conclusion our results suggest that gene expression of PAs and PAIs in early implantation sites are tissue-specific, location-sensitive and function-related.
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PMID:Plasminogen activators and inhibitors are transcribed during early macaque implantation. 1117 Aug 23

A number of experimental and clinical studies have recently underlined the importance, in acute myocardial infarction, of platelet adhesion and aggregation after plaque rupture. During clot resolution, platelet-rich thrombi are relatively resistant to fibrinolytic agents, mainly due to the release of plasminogen inhibitor-1 by platelets which are activated as a result of the increase in thrombin generation induced by plasminogen activator therapy despite heparin administration. Platelet glycoprotein (GP) IIb/IIIa integrin receptor blockers prevent platelet aggregation by blocking the final pathway of platelet activation. Thus, they also prevent the formation of an intraluminal white thrombus without affecting adhesion. Animal and human studies have shown that the potent inhibition of platelet GP IIb/IIIa receptors can lead to modest reperfusion rates even without exogenous fibrinolytic therapy. This suggests that combining the "dethrombotic" effects of a GP IIb/IIIa antagonist with lower fibrynolytic doses may result in a synergistic effect. Preclinical studies including patients with myocardial infarction have shown that such combined treatment increases the incidence, speed and durability of reperfusion. It has also been proved to be useful in improving the microcirculatory coronary flow and in facilitating subsequent percutaneous coronary interventions. In the phase III GUSTO V trial, abciximab combined with 5 + 5 U of reteplase and low-dose weight-adjusted heparin led to a 30-day mortality rate that was similar to that obtained with full-dose reteplase (10 + 10 U) and standard heparin therapy, without causing a significant increase in the incidence of intracranial hemorrhage. The results of this trial offer a rationale for alternative reperfusion therapy, although further analyses, including a 1-year follow-up, are needed to define the patient groups that are most likely to benefit from such a new regimen.
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PMID:[New strategies in the treatment of acute myocardial infarction]. 1172 6

The plasminogen activating system is important for extracellular proteolysis and plays a regulatory role in interactions with other tissue degrading systems. Studies on the plasminogen activating system in gingival crevicular fluid (GCF) as well as gingival tissue are reviewed. t-PA, u-PA, PAI-1 and PAI-2 have all been detected in GCF. Especially t-PA and PAI-2 are found in high concentrations. In tissue studies fibrinolytic activity has been found in the gingival pocket epithelium in humans and in animal studies. t-PA and PAI-2 have been detected there immunohistochemically. Local production of the PAs and PAls has been verified with in situ hybridization. In inflammation, a more intense and widespread immunohistochemical staining of t-PA and PAI-2 is seen. Higher concentrations of t-PA and PAI-2 are found in GCF but the balance between them seems to be constant. A systemically disturbed balance of the plasminogen activating system in GCF has been observed during pregnancy, with a possible protective function of PAI-2. In studies of periodontitis, the production of PAI-2 seemed to be locally lowered at impaired sites. In a study of children, a higher inflammatory response to bacterial plaque was accompanied by a higher fibrinolytic ativity in GCF samples. Bacterial LPS has been found to change the ratio of t-PA to PAI-2 in cultured gingival fibroblasts. Interactions between PAI-2 and a protease in the gingival epithelium has been verified through the immunohistochemical detection of relaxed PAI-2.
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PMID:The plasminogen activating system in periodontal health and disease. 1192 25

The best conventional fibrinolytic regimens succeed in restoring unimpeded coronary flow (i.e., TIMI grade 3 reperfusion) in only about 50% of lytic-eligible patients. In experienced hands, percutaneous coronary intervention (angioplasty + stent implantation) can restore TIMI 3 flow in more than 80% of patients; however, it is not universally available, and usually cannot be performed as promptly as fibrinolytic therapy. Researchers now recognize that one key reason fibrinolytic therapy fails is that it does not adequately address the role of platelets in both the initial formation and posttreatment recurrence of coronary thrombus activated, aggregating platelets at the site of plaque fissure or rupture form the core ("white" clot) of an intracoronary thrombus. The platelets contribute to the further development of a meshwork of fibrin, thrombin, and entrapped blood cells ("red" clot), which usually makes up the bulk of an occlusive coronary thrombus. Plasminogen activators, such as alteplase and reteplase, lyse fibrin in the red thrombus but leave the platelet-rich core intact. The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban, and eptifibatide bind to GP IIb/IIIa receptors on the surfaces of activated platelets. By preventing the receptors from binding to fibrinogen (and, hence, to each other) GP IIb/IIIa inhibitors block the "final common pathway" to platelet aggregation. Combining fibrinolysis with GP IIb/IIIa blockade to treat acute myocardial infarction could, theoretically, yield a number of benefits. It would attack both red and white components of the occlusive thrombus, help suppress the thrombotic rebound effect of fibrinolytics by preventing platelet activation in response to newly exposed thrombin, improve reperfusion and microvascular flow, reduce the incidence of postfibrinolytic hemorrhagic stroke (currently approximately 1%) if combination therapy permits use of lower dosages of fibrinolytic agents. Two phase II trials of fibrinolytic therapy plus GP IIb/IIIa blockade have recently been reported. In TIMI 14, the reduced-dose combinations of alteplase plus abciximab produced TIMI 3 rates higher than the control group. In the TIMI 14 reteplase substudy, TIMI 3 flow rates with reteplase at 90 min was 70% for standard dose reteplase alone, 70% for reteplase 5 IU + 5 IU plus abciximab, and 77% for reteplase 10 IU + 5 IU plus abciximab. In the SPEED pilot study the highest TIMI 3 rates was seen with the regimen of 5 IU + 5 IU double-bolus reteplase plus abciximab (54 vs 47%). The findings of both the SPEED and TIMI 14 trials were incorporated into the design of the large (approximately 17,000 patients) GUSTO V mortality trial, which compared standard reteplase therapy with abciximab plus low-dose reteplase. Unfortunately, the results did not confirm the favorable angiographic findings of the phase II trials reported above, because the two strategies showed the same mortality rate at 30-day follow-up. The present review will try to shed light on the "dark side of the moon" of the association between IIb/IIIa inhibitors and fibrinolytic drugs in order to understand the unexpected GUSTO V results, now matched by the ASSENT-3 disappointing results with tenecteplase plus abciximab.
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PMID:[Combination therapy for acute myocardial infarction with glycoprotein IIb/IIIa inhibitors and fibrinolysis]. 1206 94

Acute myocardial infarction may result from rupture or fissuring of atherosclerotic plaque in a coronary artery. Sometimes a different pathogenesis occurs like microembolization following lysis from ulcerated plaque or during pharmacological or interventional procedures. We describe a patient with anterior myocardial infarction treated with alteplase + abciximab (TIMI 14). At the end of thrombolytic therapy administration, we observed a marked reduction of anterior ST elevation associated with a simultaneous occurrence of ST elevation in the inferior leads, later followed by inferior Q waves. The coronary angiogram demonstrated an isolated 60% stenosis on the left anterior descending artery. This case raises the question on whether the very effective and aggressive thrombolytic treatment was paradoxically responsible for microembolization resulting in myocardial infarction extension.
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PMID:[Coronary microembolization in acute coronary syndrome: indicative hypothesis or still unknown phenomenon? Description of a clinical case]. 1240 67

Cholesterol lowering therapy markedly reduces the frequency of subsequent cardiovascular events and is associated with a modest degree of angiographic regression of atherosclerotic lesions. There is a strong association between lipids and fibrinogen, plasminogen activator-1, and activated factor VII levels. Low density lipoprotein may be thrombogenic whereas high density lipoprotein protects against thrombosis. Lipoprotein (a) may affect atherosclerosis and thrombosis mainly by binding to fibrin and attenuating the fibrin-enhanced plasminogen activation. Tissue factor-complex initiates coagulation by activating factor X and factor IX leading in the presence of calcium to the generation of thrombin. Lipid lowering treatment with statins stabilizes atheromatous plaque and has antithrombotic effects. Therefore there are links between lipids and the haemostatic mechanisms which affect atherosclerotic, vasomotor and thrombotic components of ischemic heart disease.
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PMID:Effects of lipids on thrombotic mechanisms in atherosclerosis. 1241 62

With the RT-PCR technique, human tissue-type plasminogen activator (t-PA) cDNA was amplified from human melanoma cells. The sequence was proved to be the same as those reported by foreign researchers. The t-PA cDNA containing whole reading frame was inserted into the transfer vector pBacPAK8. The constructed pBac-tPA and the linear BacPAK6 virus DNA were cotransfected with Tn-5B-1 insect cells by lipofectin-mediated transfection method. Eleven pure recombinant viruses were isolated by plaque assay, and one of them, nominated BactPA3, was selected by PCR identification and biological activity comparison. The t-PA activity expressed in serum-containing media reach the highest level at 72 h postinfection. The activity was 3.04 x 10(3) IU/ml, e.g. 1.8 x 10(4) IU/10(6) cells. The highest expression level in serum-free media was almost the same, but needed more time (at 132 h postinfection). SDS-PAGE fibrin autography showed that the molecular weight of the expressed t-PA was about 68 kDa. Its stimulation by fibrinogen, affinity with fibrin and inactivation in plasma were almost the same as the native t-PA purified from human melanoma cell culture. The half-life of t-PA expressed in serum-free media was seven minutes.
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PMID:[Expression and characterization of t-PA in insect cells]. 1254 67

The fibrinolytic system (the plasminogen activating system) is involved in several physiological and pathological processes. Through the transformation of plasminogen to the aggressive broad spectrum protease plasmin, potent enzymatic activity is released. Plasmin acts directly on connective tissue components, and indirectly by activating proforms of the metalloproteinases. The destructive potential of the fibrinolytic system may thus be of importance for the initiation and progression of periodontal diseases. Earlier studies have shown high concentrations of the plasminogen activator t-PA and its inhibitor PAI-2 in gingival crevicular fluid (GCF) as well as enhanced concentrations in areas of gingival inflammation. The aim of this study was to investigate a possible relationship between the gingival inflammatory reactivity and the fibrinolytic activity in gingival crevicular fluid. Thirty-one young individuals took part in the study. Gingival Index scores and Plaque Index scores were assessed and used to formulate a score expressing an individuals' inflammatory response to microbial plaque levels (Relative G/P score). The fibrinolytic activity of GCF was assessed with a fibrin gel lysis assay, and the levels of t-PA and PAI-2 were assayed with ELISAs. All samples showed fibrinolytic activity. A positive correlation between the fibrinolytic activity and Relative G/P score was found. Thus, in individuals with an enhanced reactivity to dental plaque, a higher plasminogen activating activity in GCF was seen. This indicates a higher potential for tissue proteolysis in these individuals, possibly facilitating spread and deeper involvement of the lesions.
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PMID:Relationship between fibrinolytic activity and gingival inflammatory reaction in young individuals. 1255 44

It is well established that inflammation is an integral feature of atherosclerosis and of the cardiovascular diseases which it underlies. Oxidative stress is also recognized as a key actor in atherogenesis, in which it is closely associated with the inflammatory response and bioactive lipid formation. Several bioactive lipids have been identified in the atherosclerotic plaque, including the potent inflammatory mediator platelet activating factor (PAF), PAF-like lipids, oxidised phospholipids (oxPL) and lysophosphatidylcholine (lyso-PC). Recent evidence has established a central role of two phospholipases (PL) in atherogenesis, the non-pancreatic Type II secretory phospholipase A(2) (sPLA(2)) and the lipoprotein-associated PLA(2)-alternatively termed as PAF-acetylhydrolase (PAF-AH). sPLA(2) is calcium-dependent and hydrolyses the sn-2 acyl group of glycerophospholipids of lipoproteins and cell membranes to produce lyso-PC and free fatty acids. It is also implicated in isoprostane production from oxPL. sPLA(2) is an acute phase reactant, which is upregulated by inflammatory cytokines and may represent a new independent risk factor for coronary heart disease. In contrast to sPLA(2), PAF-AH is calcium-independent and is specific for short acyl groups at the sn-2 position of the phospholipid substrate and with the exception of PAF, can equally hydrolyze oxPL to generate lyso-PC and oxidized fatty acids. Thus PAF-AH plays a key role in the degradation of proinflammatory oxPL and in the generation of lyso-PC and oxidized fatty acids. PAF-AH equally can also hydrolyze short-chain diacylglycerols, triacylglycerols, and acetylated alkanols, and displays a PLA(1) activity. Whereas sPLA(2) may represent a new independent risk factor for coronary artery disease, the potential relevance of PAF-AH to atherosclerosis remains the subject of debate, and recent results suggest that the potential role of the LDL-associated PAF-AH in atherogenesis may be distinct to that of the HDL-associated enzyme. This review is focused on the main structural and catalytic features of plasma PAF-AH, on the association of the enzyme with distinct lipoprotein particle subspecies, on its cellular sources, and finally on the potential significance of this lipoprotein-associated PLA(2) in cardiovascular disease.
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PMID:Inflammation, bioactive lipids and atherosclerosis: potential roles of a lipoprotein-associated phospholipase A2, platelet activating factor-acetylhydrolase. 1257 64

We describe a patient with acute myocardial infarction who showed ruptured plaque distant from the maximally stenotic lesion. In a 54-year-old male patient with acute antero-lateral myocardial infarction, coronary angiography showed a resolution of occlusive lesion with residual stenotic lesion in the middle portion of the left anterior descending artery (LAD) following t-PA administration. One month later, coronary angiography again disclosed significant stenosis of the middle LAD. Intravascular ultrasound revealed ruptured plaque that was located proximal to the maximally stenotic site which is generally considered as the culprit lesion. In this case, transient vessel occlusion occurred at the maximally stenotic site probably associated with plaque rupture distant from this lesion.
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PMID:Ruptured atherosclerotic plaque distant from maximal stenosis in acute myocardial infarction. 1258 19


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