Disease relevance of PLAT

• In most cases, the levels of expression of FGFRI and PLAT in breast tumors were comparable to their level of expression in normal mammary tissue [1].
• In the present study, we show that both FGFRI and PLAT can be amplified in breast as well as ovarian carcinomas [1].
• The analysis of PLAT and LCN2 transcripts in 12 samples obtained through EUS-guided FNA from patients with pancreatic adenocarcinoma showed significantly increased expression levels in comparison with those found in normal tissues, indicating that a sufficient amount of high quality RNA can be obtained with this technique [2].
• At all ages, the use of t-PA in patients with anterior infarctions yielded more favorable cost-effectiveness values [3].
• CONTEXT: New bolus fibrinolytics derived from the human tissue-type plasminogen activator (tPA) have emerged as a means of dissolution of occlusive thrombosis associated with acute myocardial infarction [4].

Psychiatry related information on PLAT

• Release of both t-PA and VWF from the same storage pool likely accounts for the coordinate increase in the plasma level of the 2 proteins in response to numerous stimuli, such as physical activity, beta-adrenergic agents, and 1-deamino-8d-arginine vasopressin (DDAVP) among others [5].
• On the basis of accumulated evidence, the greatest risk reduction with alteplase therapy may be in certain high risk groups, such as those with anterior infarcts, selected elderly patients and those who present late after symptom onset [6].
• Because alteplase costs approximately 30 times more than streptokinase, informed medical decision making is imperative [7].
• Release of tissue plasminogen activator (t-PA) and its interaction with plasma protease inhibitors were studied in two patients with massive defibrination, one after electroshock and soft tissue injury and the other after complicated labor; both had very severe hemorrhage [8].
• After the overnight fast the effects on t-PA and PAI had disappeared whereas at that time alcohol consumption tended to decrease platelet function [9].

High impact information on PLAT

• The concentration of t-PA antigen correlated with that of the t-PA-PAI-1 complex in a linear regression model (squared correlation coefficient, 0.80; P<0.001) [10].
• We assessed whether coronary stenting combined with the blockade of platelet glycoprotein IIb/IIIa receptors produces a greater degree of myocardial salvage than fibrinolysis with an accelerated infusion of alteplase, a tissue plasminogen activator, in patients with acute myocardial infarction [11].
• RESULTS: In the group that received a stent plus abciximab, the median size of the final infarct was 14.3 percent of the left ventricle (25th and 75th percentiles, 6.8 and 24.5 percent), as compared with a median of 19.4 percent (25th and 75th percentiles, 7.9 and 34.2 percent) in the alteplase group (P=0.02) [11].
• Mutagenesis of an AP2 DNA-binding site within a p21 promoter-luciferase reporter inhibited its activation by either AP2 transfection or TPA stimulation [12].
• In patients with angina pectoris, the levels of fibrinogen, von Willebrand factor antigen, and t-PA antigen are independent predictors of subsequent acute coronary syndromes [13].

Chemical compound and disease context of PLAT

• Lanoteplase and heparin bolus plus infusion is as effective as tPA with regard to mortality, but the rate of intracranial hemorrhage is significantly higher [4].
• Six hundred six patients with acute myocardial infarction were randomized to one of four treatment arms: (1) TPA 100 mg i.v. over 3 hours, (2) r-PA as a 15-MU single bolus, (3) r-PA as a 10-MU bolus followed by 5 MU 30 minutes later, or (4) r-PA as a 10-MU bolus followed by 10 MU 30 minutes later [14].
• The serine protease tissue-type plasminogen activator (t-PA) initiates the fibrinolytic protease cascade and plays a significant role in motor learning, memory, and neuronal cell death induced by excitotoxin and ischemia [15].
• These data provide evidence that atorvastatin reduces exogenous tPA-aggravated cerebral endothelial genes that mediate thrombosis and blood-brain barrier permeability, which could contribute to the beneficial effects of statins on thrombolytic treatment of acute stroke [16].
• In plasma, melanoma and recombinant two chain t-PA were hardly inhibited by C1-inhibitor, in contrast to melanoma and recombinant single chain t-PA which were inhibited to the same extent by endogenous C1-inhibitor as they were by purified C1-inhibitor [17].

Biological context of PLAT

• Dinucleotide repeat polymorphism at the human tissue plasminogen activator gene (PLAT) [18].
• We used a "population tube" approach to screen 10 chromosomes from each of 19 human populations for presence or absence of this Alu in the PLAT locus and found that all tested populations are dimorphic for presence/absence of this insertion [19].
• The results also show that three haplotypes at the PLAT locus accounted for nearly 90% of the chromosomes and that they could be defined by typing only two SNPs [20].
• The results also showed that the level of linkage disequilibrium was high at the PLAT locus, as demonstrated by the fact that only three haplotypes had a frequency above 5% [20].
• Multipoint linkage analysis, using a simplified pedigree structure for the family (which contains 192 individuals and two inbreeding loops), gave a maximum lod score of 12.2 for RP1 at a distance 8.1 cM proximal to PLAT in the pericentric region of the chromosome [21].

Anatomical context of PLAT

• Variant tissue-type plasminogen activator (PLAT) cDNA obtained from human endothelial cells [22].
• Using 1.2kb 3'-terminal Pst-I fragment of a full length tissue-type plasminogen activator (t-PA) cDNA clone (ptPA-8FL) and a set of rodent human somatic cell hybrids, the corresponding human gene PLAT was localized on chromosome 8 [23].
• The secretion of tissue plasminogen activator (t-PA), urokinase (u-PA) and their inhibitors by the human leukemia cell line K562 was examined [24].
• In cultured human umbilical vein endothelial cells (HUVECs), t-PA was expressed in a minority of cells and found in WP bodies by immunofluorescence [5].
• Annexin II supported t-PA-dependent generation of cell surface plasmin and the matrix-penetrating activity of human monocytes [25].

Associations of PLAT with chemical compounds

• Therefore, plasminogen bound to lysine termini on fibrin, although found to be essential for pro-UK, did not appear to serve as a substrate for t-PA [26].
• Unlike other chymotrypsin family serine proteinases, tPA is proteolytically active in a single-chain form [27].
• TPA, at concentrations > or = 2000 IU/mL, significantly inhibited shear stress-induced platelet aggregation of platelet-rich plasma without a decrease in platelet GP Ib [28].
• In vivo, C1-inhibitor bound to TPA at a rate of 553 mol-1.s-1 [29].
• The circulatory regulation of TPA and UPA secretion, clearance, and inhibition during exercise and during the infusion of isoproterenol and phenylephrine [29].

Physical interactions of PLAT

• The high-affinity binding of tPA to VSMCs resulted in an eightfold greater potential for plasmin generation than the binding of uPA, with this difference increasing to 15-fold after thrombin stimulation of the cells due to a 1.8-fold increase in tPA binding [30].
• Several findings suggest that PAI-1 is a major binding site for S478A t-PA [31].
• The increased amount of bound Plg was demonstrated to result in a similar increase in the amount of plasmin generated from the complexes by TPA [32].
• Both t-PA and the gelatin-binding domain of fibronectin have adhesive functions, and the gelatin-binding domain promotes viral transformation of fibroblasts in culture [33].
• Matrix metalloproteinase-3 (MMP-3 or stromelysin-1) specifically binds to tissue-type plasminogen activator (t-PA), without however, hydrolyzing the protein [34].

Enzymatic interactions of PLAT

• Interactions of plasminogen and tissue plasminogen activator (t-PA) with amphoterin. Enhancement of t-PA-catalyzed plasminogen activation by amphoterin [35].
• However, the specificity of the inhibitory reaction with tPA and uPA was notably higher than that for the substrate reaction catalyzed by elastase. pH dependences of k(lim) and K(0.5) obtained for tPA revealed an additional ionizable group (pKa, 6.0-6.2) affecting the reaction [36].
• Results obtained from in vitro experiments showed that urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA) can cleave single-chain HGF [37].
• Detailed interpretation of the (19)F NMR spectra of the PAI-1 mutants provides insights into the local segmental structure of the active form of the proteins and the structural changes that occur in the cleaved and t-PA complexed forms [38].
• Lanoteplase is a fibrinolytic drug derived from t-PA by deleting its fibronectin finger-like and epidermal growth factor domains and mutating Asn(117) to Gln(117) [39].

Co-localisations of PLAT

• Part of the tPA was detected in the extracellular space and colocalized with fibrin deposits. uPA antigen and mRNA were detected in association with the intimal macrophages and SMCs [40].

Regulatory relationships of PLAT

• Plasminogen bound to the latter site on fibrin was activated by t-PA and therefore is involved in the ternary complex [26].
• In the central nervous system, neuroserpin (NSP) is a serpin thought to regulate t-PA enzymatic activity [15].
• ERK signaling pathway is involved in p15INK4b/p16INK4a expression and HepG2 growth inhibition triggered by TPA and Saikosaponin a [41].
• Finally, kinetic modeling demonstrated that acylation is the rate-limiting step in thrombin inhibition by PAI-1 (k approximately 10(-3) s(-1)) and this kinetic block is alleviated by the introduction of the tPA-VR1 into thrombin (k>1 s(-1)) [42].
• The rate of transmigration was consistently higher for u-PA-expressing cells than for t-PA-expressing cells [43].

Other interactions of PLAT

• TSP, when incubated with Plg before addition to 125I-fibrin plates significantly inhibited the generation of plasmin activity by tissue plasminogen activator (TPA) in a manner that was calcium dependent [44].
• The decrease in t-PA activity in the neoplastic tissues, determined enzymatically and zymographically, was significantly correlated with an increase in PAI-1 and PAI-2, in particular in carcinomas [45].
• Neoplastic growth and metastatic spread of adenocarcinomas is characterized by a marked increase of urokinase-type plasminogen activator (u-PA) and a decrease of tissue-type plasminogen activator (t-PA) [45].
• For tPA but not for PAI-1 and vWF, this association is independent of established risk factors [46].
• Although phosphorylated extracellular signal-regulated kinase 1/2 levels in these cells cultured under estradiol deplete and replete conditions displayed no change, a significant induction was observed after TPA treatment [47].

Analytical, diagnostic and therapeutic context of PLAT

• The techniques used were whole chromosome paint (WCP) and fluorescence in situ hybridization (FISH) with three cosmid probes mapping to different parts of the p-arm (D8S7 (8p23.3), LPL (8p22) and PLAT (8p11.1)) [48].
• Increased fibrin turnover and high PAI-1 activity as predictors of ischemic events in atherosclerotic patients. A case-control study. The PLAT Group [49].
• The higher rate of stroke in women after treatment with alteplase (2.0% vs 1.9% with streptokinase and intravenous heparin) was offset by a greater relative reduction in mortality (10.3% vs 11.1%) [50].
• Alteplase versus heparin in acute pulmonary embolism: randomised trial assessing right-ventricular function and pulmonary perfusion [51].
• Northern blot hybridization and nuclear "Run-on" transcription assays demonstrated that the increase of t-PA and PAI-1 and the decrease of u-PA were associated with equivalent changes of gene template activity [52].

References