Plasminogen Activator Inhibitor 1: Physiological and Pathophysiological Roles

Physiology ◽  
2002 ◽  
Vol 17 (2) ◽  
pp. 56-61 ◽  
Author(s):  
Bernd R. Binder ◽  
Günter Christ ◽  
Florian Gruber ◽  
Nelly Grubic ◽  
Peter Hufnagl ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Density Lipoprotein Receptor ◽  
The Matrix ◽  
Activator Inhibitor ◽  
Pai 1 ◽  
Dependent Mechanism

Plasminogen activator inhibitor 1 (PAI-1) inhibits plasminogen activators (u-PA and t-PA) by forming stable complexes endocytosed via a low-density lipoprotein receptor superfamily member-dependent mechanism. PAI-1 circulates actively in plasma and latently in platelets but is also secreted and deposited into the matrix by several cells, where it participates in tissue repair processes.

scholarly journals Inhibition of plasminogen activator inhibitor-1 binding to endocytosis receptors of the low-density-lipoprotein receptor family by a peptide isolated from a phage display library

2006 ◽  
Vol 399 (3) ◽  
pp. 387-396 ◽  
Author(s):  
Jan K. Jensen ◽  
Anders Malmendal ◽  
Birgit Schiøtt ◽  
Sune Skeldal ◽  
Katrine E. Pedersen ◽  
...  
Keyword(s):  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Pai 1

The functions of the serpin PAI-1 (plasminogen activator inhibitor-1) are based on molecular interactions with its target proteases uPA and tPA (urokinase-type and tissue-type plasminogen activator respectively), with vitronectin and with endocytosis receptors of the low-density-lipoprotein family. Understanding the significance of these interactions would be facilitated by the ability to block them individually. Using phage display, we have identified the disulfide-constrained peptide motif CFGWC with affinity for natural human PAI-1. The three-dimensional structure of a peptide containing this motif (DVPCFGWCQDA) was determined by liquid-state NMR spectroscopy. A binding site in the so-called flexible joint region of PAI-1 was suggested by molecular modelling and validated through binding studies with various competitors and site-directed mutagenesis of PAI-1. The peptide with an N-terminal biotin inhibited the binding of the uPA–PAI-1 complex to the endocytosis receptors low-density-lipoprotein-receptor-related protein 1A (LRP-1A) and very-low-density-lipoprotein receptor (VLDLR) in vitro and inhibited endocytosis of the uPA–PAI-1 complex in U937 cells. We conclude that the isolated peptide represents a novel approach to pharmacological interference with the functions of PAI-1 based on inhibition of one specific molecular interaction.

Analysis of a two-domain binding site for the urokinase-type plasminogen activator–plasminogen activator inhibitor-1 complex in low-density-lipoprotein-receptor-related protein

2001 ◽  
Vol 357 (1) ◽  
pp. 289-296 ◽  
Author(s):  
Olav M. ANDERSEN ◽  
Helle H. PETERSEN ◽  
Christian JACOBSEN ◽  
S⊘ren K. MOESTRUP ◽  
Michael ETZERODT ◽  
...  
Keyword(s):  
Binding Site ◽  
Plasminogen Activator ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
Plasminogen Activator Inhibitor 1 ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Density Lipoprotein Receptor ◽  
Pai 1

The low-density-lipoprotein-receptor (LDLR)-related protein (LRP) is composed of several classes of domains, including complement-type repeats (CR), which occur in clusters that contain binding sites for a multitude of different ligands. Each ≈ 40-residue CR domain contains three conserved disulphide linkages and an octahedral Ca2+ cage. LRP is a scavenging receptor for ligands from extracellular fluids, e.g. α2-macroglobulin (α2M)–proteinase complexes, lipoprotein-containing particles and serine proteinase–inhibitor complexes, like the complex between urokinase-type plasminogen activator (uPA) and the plasminogen activator inhibitor-1 (PAI-1). In the present study we analysed the interaction of the uPA–PAI-1 complex with an ensemble of fragments representing a complete overlapping set of two-domain fragments accounting for the ligand-binding cluster II (CR3–CR10) of LRP. By ligand blotting, solid-state competition analysis and surface-plasmon-resonance analysis, we demonstrate binding to multiple CR domains, but show a preferential interaction between the uPA–PAI-1 complex and a two-domain fragment comprising CR domains 5 and 6 of LRP. We demonstrate that surface-exposed aspartic acid and tryptophan residues at identical positions in the two homologous domains, CR5 and CR6 (Asp958,CR5, Asp999,CR6, Trp953,CR5 and Trp994,CR6), are critical for the binding of the complex as well as for the binding of the receptor-associated protein (RAP)–the folding chaperone/escort protein required for transport of LRP to the cell surface. Accordingly, the present work provides (1) an identification of a preferred binding site within LRP CR cluster II; (2) evidence that the uPA–PAI-1 binding site involves residues from two adjacent protein domains; and (3) direct evidence identifying specific residues as important for the binding of uPA–PAI-1 as well as for the binding of RAP.

In Vivo Stimulation of Vascular Plasminogen Activator Inhibitor-1 Production by very Low-Density Lipoprotein Involves Transcription Factor Binding to a VLDL-Responsive Element

2000 ◽  
Vol 84 (10) ◽  
pp. 706-711 ◽  
Author(s):  
Mikko Ares ◽  
Maria Stollenwerk ◽  
Cecilia Giachelli ◽  
Marta Scatena ◽  
Anders Hamsten ◽  
...  
Keyword(s):  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Plasminogen Activator Inhibitor ◽  
High Plasma ◽  
Plasminogen Activator Inhibitor 1 ◽  
Mrna And Protein Expression ◽  
Responsive Element ◽  
Activator Inhibitor ◽  
Pai 1

SummaryHigh plasma levels of plasminogen activator inhibitor-1 (PAI-1) are associated with an increased risk of cardiovascular disease. There is also a close relation between high plasma levels of PAI-1 and hypertriglyceridemia. Cell culture studies have shown that very low density lipoprotein (VLDL) increases the production and secretion of PAI-1 in endothelial cells and hepatocytes, suggesting a possible mechanism for this association. To determine whether VLDL stimulates PAI-1 production in vascular cells also in vivo, Sprague-Dawley rats were injected intravenously with 6 mg/kg of VLDL (derived from human subjects with type IV hyperlipidemia). Previous studies have demonstrated that this results in an accumulation of human VLDL in the aorta and other arteries followed by increased nuclear factor-kappa B (NF-κB) activation. Endothelial, but not smooth muscle cells, showed a basal PAI-1 mRNA and protein expression as assessed by in situ hybridization and immunohistochemistry, respectively. Six to twenty-four hours after the VLDL injection, lipoprotein particle accumulation was seen in the aortic wall, which was accompanied by increasing PAI-1 mRNA and protein expression in endothelial and smooth muscle cells. Within the rat PAI-1 promoter we identified a sequence located at −589 to −571 with 74% homology with the recently described VLDL responsive element in the human PAI-1 promoter and located adjacent to a 4-guanosine motif presumably corresponding to the human 4G/5G polymorphism. Transient transfection studies showed that VLDL exerts its stimulatory effects on rat PAI-1 gene expression in vascular cells by interaction with promoter sequences located within bp −656 and −505. Electrophoretic mobility shift assays showed that VLDL increases the binding of as yet incompletely characterized factors to this response element. Taken together these observations support a direct influence of VLDL on vascular PAI-1 gene expression in vivo. This stimulation is exerted on the level of PAI-1 gene transcription, and involves transcription factor binding to a VLDL responsive element adjacent to a 4G motif within the PAI-1 promoter.

Sign in / Sign up

Export Citation Format

Share Document