3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling

BACKGROUND AND PURPOSE: We investigated the effects of a synthetic flavonol, 3′,4′-dihydroxyflavonol (DiOHF) on the expression of monocyte chemoattractant protein-1 (MCP-1) in rat vascular smooth muscle cells. EXPERIMENTAL APPROACH: MCP-1 expression was assessed by quantitative real-time PCR and pro...

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Prif Awduron: Jiang, F, Guo, N, Dusting, GJ
Fformat: Erthygl
Iaith:English
Cyhoeddwyd: Blackwell Publishing Ltd 2009
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Research Papers
Mynediad Ar-lein:https://ncbi.nlm.nih.gov/pmc/articles/PMC2707972/
https://ncbi.nlm.nih.gov/pubmed/19371329
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1111/j.1476-5381.2009.00199.x
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spelling pubmed-27079722010-06-01 3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling Jiang, F Guo, N Dusting, GJ Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: We investigated the effects of a synthetic flavonol, 3′,4′-dihydroxyflavonol (DiOHF) on the expression of monocyte chemoattractant protein-1 (MCP-1) in rat vascular smooth muscle cells. EXPERIMENTAL APPROACH: MCP-1 expression was assessed by quantitative real-time PCR and protein phosphorylation by immunoprecipitation and Western blots. KEY RESULTS: DiOHF (1–30 µmol·L(−1)) concentration-dependently reduced MCP-1 expression in both quiescent cells and cells stimulated with platelet-derived growth factor (PDGF) or interleukin 1-β. The effect of DiOHF was associated with a suppression of focal adhesion kinase (FAK)-mediated signalling. In vitro kinase assays demonstrated that DiOHF is a potent inhibitor of FAK kinase activity (EC(50)= 2.4 µmol·L(−1)). Expression of FAK-related non-kinase reduced basal MCP-1 expression, but not that induced by PDGF or interleukin 1-β. DiOHF also inhibited autophosphorylation of PDGF receptors. The PDGF receptor inhibitor AG-1296 potently suppressed basal and PDGF-induced MCP-1 expression. Inhibition of extracellular signal-regulated kinase activation by DiOHF, either directly or indirectly, may also be involved in its effects on MCP-1 expression. DiOHF had no inhibitory effect on either p38 or nuclear factor-κB activation. Moreover, DiOHF inhibited smooth muscle cell spreading (a FAK-mediated response) and proliferation. CONCLUSIONS AND IMPLICATIONS: This is the first report on a flavonoid compound (DiOHF) that is a potent FAK inhibitor. DiOHF also inhibits PDGF receptor autophosphorylation. These effects underlie the inhibitory action of DiOHF on MCP-1 expression in smooth muscle cells. Our results suggest that DiOHF might be a useful tool for dissection of the (patho)physiological roles of FAK signalling. British Journal of Pharmacology (2009) 157, 597–606; doi:10.1111/j.1476-5381.2009.00199.x; published online 9 April 2009 Blackwell Publishing Ltd 2009-06 2009-04-09 /pmc/articles/PMC2707972/ /pubmed/19371329 http://dx.doi.org/10.1111/j.1476-5381.2009.00199.x Text en Journal compilation © 2009 The British Pharmacological Society
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Research Papers
spellingShingle Research Papers
Jiang, F
Guo, N
Dusting, GJ
3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
description BACKGROUND AND PURPOSE: We investigated the effects of a synthetic flavonol, 3′,4′-dihydroxyflavonol (DiOHF) on the expression of monocyte chemoattractant protein-1 (MCP-1) in rat vascular smooth muscle cells. EXPERIMENTAL APPROACH: MCP-1 expression was assessed by quantitative real-time PCR and protein phosphorylation by immunoprecipitation and Western blots. KEY RESULTS: DiOHF (1–30 µmol·L(−1)) concentration-dependently reduced MCP-1 expression in both quiescent cells and cells stimulated with platelet-derived growth factor (PDGF) or interleukin 1-β. The effect of DiOHF was associated with a suppression of focal adhesion kinase (FAK)-mediated signalling. In vitro kinase assays demonstrated that DiOHF is a potent inhibitor of FAK kinase activity (EC(50)= 2.4 µmol·L(−1)). Expression of FAK-related non-kinase reduced basal MCP-1 expression, but not that induced by PDGF or interleukin 1-β. DiOHF also inhibited autophosphorylation of PDGF receptors. The PDGF receptor inhibitor AG-1296 potently suppressed basal and PDGF-induced MCP-1 expression. Inhibition of extracellular signal-regulated kinase activation by DiOHF, either directly or indirectly, may also be involved in its effects on MCP-1 expression. DiOHF had no inhibitory effect on either p38 or nuclear factor-κB activation. Moreover, DiOHF inhibited smooth muscle cell spreading (a FAK-mediated response) and proliferation. CONCLUSIONS AND IMPLICATIONS: This is the first report on a flavonoid compound (DiOHF) that is a potent FAK inhibitor. DiOHF also inhibits PDGF receptor autophosphorylation. These effects underlie the inhibitory action of DiOHF on MCP-1 expression in smooth muscle cells. Our results suggest that DiOHF might be a useful tool for dissection of the (patho)physiological roles of FAK signalling. British Journal of Pharmacology (2009) 157, 597–606; doi:10.1111/j.1476-5381.2009.00199.x; published online 9 April 2009
author Jiang, F
Guo, N
Dusting, GJ
author_facet Jiang, F
Guo, N
Dusting, GJ
author_sort Jiang, F
title 3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
title_short 3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
title_full 3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
title_fullStr 3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
title_full_unstemmed 3′,4′-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
title_sort 3′,4′-dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and pdgf receptor signalling
publisher Blackwell Publishing Ltd
publisher_facet Blackwell Publishing Ltd
publishDate 2009
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2707972/
https://ncbi.nlm.nih.gov/pubmed/19371329
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1111/j.1476-5381.2009.00199.x
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