PMID- 19371329
OWN - NLM
STAT- MEDLINE
DCOM- 20091015
LR  - 20211020
IS  - 1476-5381 (Electronic)
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 157
IP  - 4
DP  - 2009 Jun
TI  - 3',4'-Dihydroxyflavonol down-regulates monocyte chemoattractant protein-1 in 
      smooth muscle: role of focal adhesion kinase and PDGF receptor signalling.
PG  - 597-606
LID - 10.1111/j.1476-5381.2009.00199.x [doi]
AB  - 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 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. 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.
FAU - Jiang, F
AU  - Jiang F
AD  - Bernard O'Brien Institute of Microsurgery, University of Melbourne, Victoria, 
      Australia. fjiang@unimelb.edu.au
FAU - Guo, N
AU  - Guo N
FAU - Dusting, G J
AU  - Dusting GJ
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20090409
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Chemokine CCL2)
RN  - 0 (Cytokines)
RN  - 0 (Flavonols)
RN  - 0 (NF-kappa B)
RN  - EC 2.7.1.- (FAK-related nonkinase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 2.7.10.1 (Receptors, Platelet-Derived Growth Factor)
RN  - EC 2.7.10.2 (Focal Adhesion Protein-Tyrosine Kinases)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1)
RN  - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases)
RN  - R1I1R1C88V (3',4'-dihydroxyflavonol)
SB  - IM
MH  - Animals
MH  - Cell Movement/drug effects
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Chemokine CCL2/*biosynthesis
MH  - Cytokines/pharmacology
MH  - Down-Regulation/*drug effects
MH  - Flavonols/*pharmacology
MH  - Focal Adhesion Protein-Tyrosine Kinases/*antagonists & inhibitors/physiology
MH  - Male
MH  - Mitogen-Activated Protein Kinase 1/metabolism
MH  - Muscle, Smooth, Vascular/*drug effects/metabolism
MH  - NF-kappa B/metabolism
MH  - Phosphorylation/drug effects
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors/biosynthesis
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, Platelet-Derived Growth Factor/metabolism
MH  - p38 Mitogen-Activated Protein Kinases/metabolism
PMC - PMC2707972
EDAT- 2009/04/18 09:00
MHDA- 2009/10/16 06:00
PMCR- 2010/06/01
CRDT- 2009/04/18 09:00
PHST- 2009/04/18 09:00 [entrez]
PHST- 2009/04/18 09:00 [pubmed]
PHST- 2009/10/16 06:00 [medline]
PHST- 2010/06/01 00:00 [pmc-release]
AID - BPH199 [pii]
AID - 10.1111/j.1476-5381.2009.00199.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 2009 Jun;157(4):597-606. doi: 10.1111/j.1476-5381.2009.00199.x. 
      Epub 2009 Apr 9.