Phosphoinositide 3-kinase is a novel target of piceatannol for inhibiting PDGF-BB-induced proliferation and migration in human aortic smooth muscle cells.
OBJECTIVE
Abnormal migration and proliferation of human aortic smooth muscle cells (HASMCs) to the intima causes intimal thickening of the aorta, which is strongly related to the development of atherosclerosis. Previous studies have suggested that red wine polyphenols, particularly resveratrol, have great protective effects against cardiovascular diseases. Here, we compared the anti-atherosclerotic effect of piceatannol, a metabolite of resveratrol, and its underlying mechanisms.


RESULTS
We demonstrated that piceatannol inhibited platelet-derived growth factor (PDGF)-BB-induced cell migration using a modified Boyden chamber assay and wound healing assay. Western blot analysis showed that PDGF-BB-induced phosphorylation of Akt, p70S6K, and p38 was inhibited by piceatannol, but not resveratrol. In vitro and ex vivo phosphoinositide 3-kinase (PI3K) assays demonstrated that piceatannol suppressed PI3K activity more effectively than resveratrol. PDGF-BB-induced migration and proliferation of HASMCs were inhibited by treatment with a commercial PI3K inhibitor, LY294002. Both in vitro and ex vivo pull-down assays revealed that piceatannol directly binds with sepharose 4B-PI3K beads in an ATP-competitive manner.


CONCLUSIONS
The results of the present study demonstrate that piceatannol directly binds with PI3K in an ATP-competitive manner and suppresses PI3K activity with anti-atherosclerotic effects.
Choi
Keun Hwa
KH
Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.
Kim
Jong-Eun
JE
Song
Nu Ry
NR
Son
Joe Eun
JE
Hwang
Mun Kyung
MK
Byun
Sanguine
S
Kim
Jong Hun
JH
Lee
Ki Won
KW
Lee
Hyong Joo
HJ
D000255:Adenosine Triphosphate / Q000378:metabolism; D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D001011:Aorta / Q000166:cytology; D000077214:Becaplermin; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D020574:Proto-Oncogene Proteins c-sis; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D013267:Stilbenes / Q000494:pharmacology*; D000072377:Syk Kinase
D000255:Adenosine Triphosphate; D043925:Angiogenesis Inducing Agents; D000077214:Becaplermin; D004791:Enzyme Inhibitors; D024581:Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating); D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010982:Platelet-Derived Growth Factor; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020574:Proto-Oncogene Proteins c-sis; D000077185:Resveratrol; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D013267:Stilbenes; D000072377:Syk Kinase; C041525:3,3',4,5'-tetrahydroxystilbene; C000606896:SYK protein, human