3',4'-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: role of focal adhesion kinase and PDGF receptor signalling
| Autor: | F, Jiang, N, Guo, G J, Dusting |
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| Rok vydání: | 2009 |
| Předmět: |
Male
Mitogen-Activated Protein Kinase 1 Flavonols NF-kappa B Down-Regulation Protein-Tyrosine Kinases p38 Mitogen-Activated Protein Kinases Research Papers Muscle Smooth Vascular Rats Rats Sprague-Dawley Cell Movement Focal Adhesion Protein-Tyrosine Kinases Animals Cytokines Receptors Platelet-Derived Growth Factor Phosphorylation Cells Cultured Chemokine CCL2 Cell Proliferation |
| Zdroj: | British journal of pharmacology. 157(4) |
| ISSN: | 1476-5381 |
| Popis: | 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.MCP-1 expression was assessed by quantitative real-time PCR and protein phosphorylation by immunoprecipitation and Western blots.DiOHF (1-30 micromol x L(-1)) concentration-dependently reduced MCP-1 expression in both quiescent cells and cells stimulated with platelet-derived growth factor (PDGF) or interleukin 1-beta. 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 micromol x L(-1)). Expression of FAK-related non-kinase reduced basal MCP-1 expression, but not that induced by PDGF or interleukin 1-beta. 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-kappaB activation. Moreover, DiOHF inhibited smooth muscle cell spreading (a FAK-mediated response) and proliferation.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. |
| Databáze: | OpenAIRE |
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