title: Phosphoinositide 3-kinase is a novel target of piceatannol for inhibiting PDGF-BB-induced proliferation and migration in human aortic smooth muscle cells.
abstract: 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.
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea.
authors.forename: Keun Hwa
authors.initials: KH
authors.lastname: Choi
authors.forename: Jong-Eun
authors.initials: JE
authors.lastname: Kim
authors.forename: Nu Ry
authors.initials: NR
authors.lastname: Song
authors.forename: Joe Eun
authors.initials: JE
authors.lastname: Son
authors.forename: Mun Kyung
authors.initials: MK
authors.lastname: Hwang
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Jong Hun
authors.initials: JH
authors.lastname: Kim
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
mesh_terms: 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
chemical_list: 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