Delphinidin and cyanidin inhibit PDGF(AB)-induced VEGF release in vascular smooth muscle cells by preventing activation of p38 MAPK and JNK.
OBJECTIVE
Red wine polyphenols (RWPs) inhibit the expression of vascular endothelial growth factor (VEGF), a major pro-angiogenic and pro-atherosclerotic factor, in vascular smooth muscle cells (VSMCs). The aim of this study was to identify which red wine polyphenols were inhibitory and to determine the mechanism underlying the inhibitory effects.


METHODS
Release of VEGF stimulated by platelet derived growth factor(AB) (PDGF(AB)), from human aortic VSMCs was measured by immunoassay and phosphorylation of kinases by Western blot analysis. The direct antioxidant properties of polyphenols were determined by electron paramagnetic resonance and the cellular formation of reactive oxygen species (ROS) by dichlorofluorescein.


RESULTS
The inhibitory effect of RWPs on PDGF(AB)-induced release of VEGF was mimicked by delphinidin but not by quercetin, catechins, resveratrol, gallic acid or caffeic acid. In the anthocyanin class, not only delphinidin but also cyanidin prevented VEGF release whereas malvidin and peonidin were without effect. RWPs, delphinidin and cyanidin directly scavenged ROS and prevented the PDGF(AB)-induced formation of ROS in VSMCs. Malvidin and peonidin did not scavenge ROS but prevented the cellular formation of ROS. Although the p38 MAPK, ERK1/2 and JNK pathways have been involved in the PDGF(AB)-induced expression of VEGF, in our experiments, only phosphorylation of p38 MAPK and JNK was inhibited by RWPs, delphinidin and cyanidin.


CONCLUSIONS
Anthocyanins presenting a hydroxyl residue at position 3' are able to inhibit PDGF(AB)-induced VEGF expression by preventing activation of p38 MAPK and JNK in VSMCs.
Oak
M-H
MH
Dépt Pharmacologie et Physicochimie, Faculté de Pharmacie, Institut Gilbert-Laustriat, UMR 7175, Université Louis Pasteur (Strasbourg I), Strasbourg, France.
Bedoui
J E
JE
Madeira
S V F
SV
Chalupsky
K
K
Schini-Kerth
V B
VB
D000872:Anthocyanins / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology
D000872:Anthocyanins; D000975:Antioxidants; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; C095477:platelet-derived growth factor AB; C017154:cyanidin; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C017185:delphinidin