Tissue-type plasminogen activator binds to and is inhibited by surface-bound lipoprotein(a) and low-density lipoprotein

Biochemistry ◽  
1991 ◽  
Vol 30 (27) ◽  
pp. 6671-6677 ◽  
Author(s):  
Daniel I. Simon ◽  
Gunther M. Fless ◽  
Angelo M. Scanu ◽  
Joseph Loscalzo
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Low Density ◽  
Tissue Type Plasminogen Activator ◽  
Lipoprotein A ◽  
Type Plasminogen Activator

Tissue-type plasminogen activator-binding RNA aptamers inhibiting low-density lipoprotein receptor family-mediated internalisation

2015 ◽  
Vol 114 (07) ◽  
pp. 139-149 ◽  
Author(s):  
Kenneth A. Bøtkjær ◽  
Nicky Helsen ◽  
Peter A. Andreasen ◽  
Daniel M. Dupont ◽  
Nils Bjerregaard
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Ldl Receptor ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Clot Lysis ◽  
Low Density ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Receptor Family

SummaryRecombinant tissue-type plasminogen activator (tPA, trade name Alteplase), currently the only drug approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of cerebral ischaemic stroke, has been implicated in a number of adverse effects reportedly mediated by interactions with the low-density lipo-protein (LDL) family receptors, including neuronal cell death and an increased risk of cerebral haemorrhage. The tissue-type plasminogen activator is the principal initiator of thrombolysis in human physiology, an effect that is mediated directly via localised activation of the plasmin zymogen plasminogen at the surface of fibrin clots in the vascular lumen. Here, we sought to identify a ligand to tPA capable of inhibiting the relevant LDL family receptors without interfering with the fibrinolytic activity of tPA. Systematic evolution of ligands by exponential enrichment (SELEX) was employed to isolate tPA-binding RNA aptamers, which were characterised in biochemical assays of tPA association to low density lipoprotein receptor-related protein-1 (LRP-1, an LDL receptor family member); tPA-mediated in vitro and ex vivo clot lysis; and tPA-mediated plasminogen activation in the absence and presence of a stimulating soluble fibrin fragment. Two aptamers, K18 and K32, had minimal effects on clot lysis, but were able to efficiently inhibit tPA-LRP-1 association and LDL receptor family-mediated endocytosis in human vascular endothelial cells and astrocytes. These observations suggest that coadministration alongside tPA may be a viable strategy to improve the safety of thrombolytic treatment of cerebral ischaemic stroke by restricting tPA activity to the vascular lumen.

Cellular Degradation of Free and Inhibitor-bound Tissue-type Plasminogen Activator

2000 ◽  
Vol 83 (02) ◽  
pp. 290-296 ◽  
Author(s):  
Chantal Camani ◽  
Olivier Gavin ◽  
Egbert Kruithof
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
Density Lipoprotein Receptor ◽  
Activator Inhibitor Type ◽  
Pai 1

SummaryThe low density lipoprotein receptor-related protein (LRP) is a multiligand clearance receptor that removes free tissue-type plasminogen activator (t-PA) or complexes of t-PA with plasminogen activator inhibitor type 1 (PAI-1) from the blood circulation or the pericellular space. Co-receptors are essential for LRP-mediated clearance of several ligands (e.g. glycosaminoglycans for thrombin/protease nexin and lipoprotein lipase, and the urokinase receptor for urokinase/PAI-1 complexes). The present study was undertaken to investigate whether LRP-mediated t-PA clearance requires a co-receptor as well.In five cell lines from different organs and species degradation of t-PA and t-PA/PAI-1 was mediated by LRP (or LRP-like receptors). No degradation of t-PA and t-PA/PAI-1 occurred in THP-1 or U-937 human monocyte-like cells, despite the presence of functional LRP. As glycosaminoglycans can bind t-PA and PAI-1 we investigated whether they are involved in t-PA/PAI-1 degradation. Pre-treatment of COS cells or HT1080 cells with chlorate, an inhibitor of glycosaminoglycan sulfation, did not decrease t-PA/PAI-1 degradation. Furthermore, CHO cells genetically deficient in glycosaminoglycans efficiently degraded t-PA/PAI-1. Thus it is unlikely that glycosaminoglycans are co-receptors for degradation of t-PA or t-PA/PAI-1.This study indicates that THP-1 and U-937 cells lack a critical component (co-receptor?) for the LRP-mediated degradation of t-PA. Abbreviations: LRP, low density lipoprotein receptor-related protein; PAI-1, plasminogen activator inhibitor type 1; RAP, receptor-associated protein; t-PA, tissue-type plasminogen activator; u-PA, urokinase; u-PAR, urokinase receptor.

Monoclonal Antibodies against the Human Mannose Receptor that Inhibit the Binding of Tissue-type Plasminogen Activator

1997 ◽  
Vol 77 (04) ◽  
pp. 718-724 ◽  
Author(s):  
Marrie Barrett-Bergshoeff ◽  
Femke Noorman ◽  
Rogier Bos ◽  
Dingeman C Rijken
Keyword(s):  
Monoclonal Antibodies ◽  
Western Blot ◽  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Placental Tissue ◽  
Mannose Receptor ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryTo study the role of the mannose receptor in cellular uptake and degradation of tissue-type plasminogen activator (t-PA), a set of five monoclonal antibodies (Moab) was generated against the mannose receptor isolated from human placental tissue.All Moab specifically recognised the 175 kDa mannose receptor in a crude placenta extract, as shown in Western blot analysis. By use of im- munohistochemistry, we showed that in human placenta only the Hof- bauer cells (fetal macrophages) express the mannose receptor. Epitope competition experiments indicated that the Moab bound to at least two different epitopes on the receptor molecule. Moab 14-3, 14-5, and 15-2, which are directed against one of these epitopes, strongly inhibited the interaction between the purified mannose receptor and t-PA. These Moab also inhibited mannose receptor-mediated degradation of t-PA by cultured human macrophages. The low density lipoprotein receptor-related protein (LRP) mediated t-PA degradation was not affected by the Moab.It is concluded that the Moab are useful for studying the expression of the human mannose receptor in Western blot and in immunohisto-chemistry, and for studying the interactions between the human mannose receptor and the mannose-containing ligand t-PA.

The Relationship of Various Factors in the Pathogenesis of Atherosclerosis

1998 ◽  
Vol 4 (2) ◽  
pp. 105-110 ◽  
Author(s):  
Hüseyin Sönmez ◽  
Selma Süer ◽  
Turgut Ulutin ◽  
Emine Kökoglu ◽  
Nergiz Uçişik
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Tissue Type ◽  
Control Group ◽  
Low Density ◽  
Lipid Parameters ◽  
Pai 1

In this study we investigated the levels of lipid parameters, fibronectin, tissue-type plasminogen activator and plasminogen activator inhibitor (t-PA-PAI-1) complex and si alidase in patients with coronary heart disease and a control group. Total cholesterol, triglyceride, low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) cholesterol and lipoprotein Lp(a), levels in patients with coronary heart disease were found to be significantly higher than in the control group (p < .001). High-density lipoprotein (HDL) cholesterol levels in patient group were significantly lower than control group (p < .001). Plasma fibronectin and t-PA-PAI-1 complex levels in patients with coronary heart disease were found to be significantly higher than control group (p < .05 and p < .001, respectively). In addition, we found that serum sialidase levels in patients with coronary heart disease were significantly higher than in the control group (p < .001). The electrophoretic mobility of lipoproteins from patients with coronary heart dis ease was found to be greater than those from the control group. As a result Lp(a) may play an important role in the pathogen esis of atherosclerosis by causing foam cell formation because of interacting with LDL or fibronectin and by interfering with the fibrinolytic system because of binding to plasminogen re ceptors. In addition, modifications of Lp(a) (including desi alylation) may effect these events. Key words: Coronary heart disease—tPA-PAI-1 complex-Fibronectin-sialidase-Lipid parameters.

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