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Cardiovascular Research Advance Access first published online on November 3, 2009
This version [Corrected Proof] published online on November 23, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp359
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Phosphoinositide-3-kinase is a novel target of piceatannol for inhibiting PDGF-BB-induced proliferation and migration in human aortic smooth muscle cells

Keun Hwa Choi1,{dagger}, Jong-Eun Kim1,{dagger}, Nu Ry Song1,{dagger}, Joe Eun Son1, Mun Kyung Hwang1,2, Sanguine Byun1,2, Jong Hun Kim2, Ki Won Lee2,* and Hyong Joo Lee1,*

1 Major in Biomodulation, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-921, Republic of Korea
2 Department of Bioscience and Biotechnology, Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea

* Corresponding author. Tel: +82 2 880 4860 (H.J.L.)/+82 2 2049 6178 (K.W.L.); Fax: +82 2 873 5095 (H.J.L.)/+82-2-3436-6178 (K.W.L.); Email: leehyjo{at}snu.ac.kr (H.J.L.)/kiwon{at}konkuk.ac.kr (K.W.L.)

Aims: 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.

Methods and 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.

Conclusion: 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.

KEYWORDS Phosphoinositide-3-kinase; Piceatannol; Platelet-derived growth factor; Migration; Atherosclerosis

Time for primary review: 38 days

{dagger} The first three authors contributed equally to the study.


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