Red wine polyphenols inhibit vascular smooth muscle cell migration through two distinct signaling pathways.
BACKGROUND
Red wine polyphenols (RWPs) have been shown to have an antiatherogenic activity mainly through antioxidative effects on LDL oxidation. Although vascular smooth muscle cell (SMC) migration is critical to atherosclerosis formation, the effect of RWPs on SMC migration has not been elucidated. In this study, we investigated whether RWPs could affect the migration of cultured SMCs stimulated by growth factors.


RESULTS
RWP concentration dependently inhibited platelet-derived growth factor (PDGF)-BB-induced and serum-induced SMC migration in wounding assay and Boyden chamber assay. However, these inhibitory effects of RWPs were not seen in serum-stimulated vascular endothelial cell migration in either assay. Moreover, specific inhibitors of phosphatidylinositol-3' kinase (PI3K) and p38 mitogen-activated protein kinase (p38(MAPK)), but not of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), reduced PDGF-BB-induced SMC migration. To elucidate the signaling mechanism underlying the RWP effects, we investigated the effects of RWPs on the activity of PI3K and the phosphorylation of MAPK pathways in PDGF-BB-stimulated SMCs. RWPs inhibited the PI3K activity and p38(MAPK) phosphorylation, but not ERK1/2 phosphorylation, in a concentration-dependent manner. Moreover, the phosphorylation of MKK3/6, an upstream kinase of p38(MAPK), was also inhibited by RWP treatment in a concentration-dependent manner, suggesting that the inhibitory effect of RWPs on the p38(MAPK) pathway works upstream of MKK3/6. The concentration-effect relationship of RWPs necessary for the inhibition of PI3K and p38(MAPK) pathways was similar to that of cell migration assays.


CONCLUSIONS
RWPs inhibit the SMC migration through the inhibition of 2 distinct signaling pathways and thus exert antiatherogenic actions.
Iijima
Katsuya
K
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Yoshizumi
Masao
M
Hashimoto
Masayoshi
M
Akishita
Masahiro
M
Kozaki
Koichi
K
Ako
Junya
J
Watanabe
Tokumitsu
T
Ohike
Yumiko
Y
Son
Bokyung
B
Yu
Jing
J
Nakahara
Koichi
K
Ouchi
Yasuyoshi
Y
D000818:Animals; D000077214:Becaplermin; D001798:Blood Proteins / Q000494:pharmacology; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects; D015194:Diffusion Chambers, Culture; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects*; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D059808:Polyphenols; D020574:Proto-Oncogene Proteins c-sis; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D014920:Wine; D048051:p38 Mitogen-Activated Protein Kinases
D001798:Blood Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010636:Phenols; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D011108:Polymers; D059808:Polyphenols; D020574:Proto-Oncogene Proteins c-sis; D011994:Recombinant Proteins; D000077214:Becaplermin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases