Document Detail


Inhibition of vascular smooth muscle cell proliferation by a novel fibroblast growth factor receptor antagonist.
MedLine Citation:
PMID:  11744033     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: One of the key events in post-angioplasty restenosis is the migration and proliferation of medial smooth muscle cells leading to neo-intima formation. This phase is mediated by several growth factors, mainly platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2/bFGF) and heparin-binding epidermal growth factor (HB-EGF). In this study, we have focused on the role of FGF2, which requires heparan sulfate proteoglycans (HSPG) as cofactors for binding and activation of its cell surface tyrosine kinase receptor. The aim of this study was to identify and explore the effect of novel FGF antagonists on vascular smooth muscle cell (VSMC) proliferation. METHODS: We have recently identified a novel class of small, positively charged molecules sharing a porphyrin core as inhibitors of FGF2 and vascular endothelial growth factor (VEGF) activity. Here we investigated the inhibitory effect of these compounds on VSMC proliferation and their effect on heparin-induced FGF receptor activity. RESULTS: We found that these molecules exert a marked inhibitory effect on FGF2-mediated smooth muscle cell (SMC) proliferation, manifested by reduced cell growth and DNA synthesis, which occurred in a dose-dependent manner with an IC(50) of approximately 1 microM of inhibitor. We demonstrate that the molecule, 5, 10, 15, 20-tetrakis (methyl-4-pyridyl)-21H, 23H-porphine tetra-p-tosylate salt (TMPP), inhibits binding of radiolabeled FGF2 to SMCs and to soluble FGF receptor 1 (FGFR1) in a manner that interferes with both ligand and receptor interactions with heparin, thereby blocking growth factor mediated SMC proliferation. CONCLUSION: We have identified an FGF antagonist, which may serve in clinical practice as a preventive measure of restenosis.
Authors:
Amit Segev; David Aviezer; Michal Safran; Zeev Gross; Avner Yayon
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cardiovascular research     Volume:  53     ISSN:  0008-6363     ISO Abbreviation:  Cardiovasc. Res.     Publication Date:  2002 Jan 
Date Detail:
Created Date:  2001-12-17     Completed Date:  2002-05-30     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  0077427     Medline TA:  Cardiovasc Res     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  232-41     Citation Subset:  IM    
Affiliation:
Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 76100, Israel.
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MeSH Terms
Descriptor/Qualifier:
Animals
Aorta
Binding, Competitive
Cattle
Cell Division / drug effects
Cells, Cultured
DNA / biosynthesis
Depression, Chemical
Fibroblast Growth Factor 2 / metabolism,  pharmacology*
Heparin / metabolism,  pharmacology
Muscle, Smooth, Vascular / cytology*,  drug effects
Porphyrins / pharmacology*
Protein Binding
Receptors, Fibroblast Growth Factor / antagonists & inhibitors*
Chemical
Reg. No./Substance:
0/Porphyrins; 0/Receptors, Fibroblast Growth Factor; 103107-01-3/Fibroblast Growth Factor 2; 38673-65-3/tetra(4-N-methylpyridyl)porphine; 9005-49-6/Heparin; 9007-49-2/DNA

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