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, G. (2009). 3',4'-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in smooth muscle: Role of focal adhesion kinase and PDGF receptor signalling. British Journal of Pharmacology,157(4), 597-606. United Kingdom: John Wiley & Sons. Retrieved from https://doi.org/10.1111/j.1476-5381.2009.00199.x
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 (EC50= 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.
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