Linked Life Data

12082110

Source:http://linkedlifedata.com/resource/pubmed/id/12082110

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
36
pubmed:dateCreated
2002-9-2
pubmed:abstractText
The adhesive glycoprotein vitronectin (VN) forms a function-stabilizing complex with plasminogen activator inhibitor-1 (PAI-1), the major fibrinolysis inhibitor in both plasma and vessel wall connective tissue. VN also interacts with two-chain high molecular weight kininogen (HKa), particularly its His-Gly-Lys-rich domain 5, and both HKa and PAI-1 are antiadhesive factors that have been shown to compete for binding to VN. In this study the influence of HKa and domain 5 on the antifibrinolytic function of PAI-1 was investigated. In a purified system, HKa and particularly domain 5 inhibited the binding of PAI-1 to VN and promoted PAI-1 displacement from both isolated VN as well as subendothelial extracellular matrix-associated VN. The sequence Gly(486)-Lys(502) of HKa domain 5 was identified as responsible for this inhibition. Although having no direct effect on PAI-1 activity itself, HKa domain 5 or the peptide Gly(486)-Lys(502) markedly destabilized the VN.PAI-1 complex interaction, resulting in a significant reduction of PAI-1 inhibitory function on plasminogen activators, resembling the effect of VN antibodies that prevent stabilization of PAI-1. Furthermore, high affinity fibrin binding of PAI-1 in the presence of VN as well as the VN-dependent fibrin clot stabilization by the inhibitor were abrogated in the presence of the kininogen forms mentioned. Taken together, our data indicate that the peptide Gly(486)-Lys(502) derived from domain 5 of HKa serves to interfere with PAI-1 function. Based on these observations potential low molecular weight PAI-1 inhibitors could be designed for the use in therapeutic interventions against thromboembolic complications.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Sep
pubmed:issn
0021-9258
pubmed:author
pubmed:issnType
Print
pubmed:day
6
pubmed:volume
277
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
32677-82
pubmed:dateRevised
2009-11-19
pubmed:meshHeading
pubmed-meshheading:12082110-Binding, Competitive, pubmed-meshheading:12082110-Cells, Cultured, pubmed-meshheading:12082110-Dose-Response Relationship, Drug, pubmed-meshheading:12082110-Endothelium, Vascular, pubmed-meshheading:12082110-Extracellular Matrix, pubmed-meshheading:12082110-Fibrin, pubmed-meshheading:12082110-Fibrinolysin, pubmed-meshheading:12082110-Fibrinolytic Agents, pubmed-meshheading:12082110-Glycine, pubmed-meshheading:12082110-Humans, pubmed-meshheading:12082110-Kinetics, pubmed-meshheading:12082110-Kininogens, pubmed-meshheading:12082110-Lysine, pubmed-meshheading:12082110-Plasminogen Activator Inhibitor 1, pubmed-meshheading:12082110-Protein Binding, pubmed-meshheading:12082110-Protein Isoforms, pubmed-meshheading:12082110-Protein Structure, Tertiary, pubmed-meshheading:12082110-Signal Transduction, pubmed-meshheading:12082110-Umbilical Veins, pubmed-meshheading:12082110-Vitronectin
pubmed:year
2002
pubmed:articleTitle
A novel antithrombotic role for high molecular weight kininogen as inhibitor of plasminogen activator inhibitor-1 function.
pubmed:affiliation
Institute for Biochemistry, Third Department of Internal Medicine, Justus Liebig University, Giessen D-35392, Germany. triantafyllos.chavakis@innere.med.uni-giessen.de
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't