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J. Biol. Chem., Vol. 281, Issue 47, 36280-36288, November 24, 2006

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Ginsenoside-Rg1 Induces Vascular Endothelial Growth Factor Expression through the Glucocorticoid Receptor-related Phosphatidylinositol 3-Kinase/Akt and -Catenin/T-cell Factor-dependent Pathway in Human Endothelial Cells^*

Kar Wah Leung, Yuen Lam Pon, Ricky N. S. Wong, and Alice S. T. Wong¹

From the Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China and the Department of Zoology, University of Hong Kong, Hong Kong, China

Ginsenoside-Rg1, the most prevalent active constituent of ginseng, is a potent proangiogenic factor of vascular endothelial cells. This suggests that Rg1 may be a new modality for angiotherapy. Rg1 can activate the glucocorticoid receptor (GR). However, the regulatory steps downstream from GR that promote Rg1-induced angiogenesis have not been elucidated. Here we showed for the first time that Rg1 was a potent stimulator of vascular endothelial growth factor (VEGF) expression in human umbilical vein endothelial cells, and importantly this induction was mediated through a phosphatidylinositol 3-kinase (PI3K)/Akt and -catenin/T-cell factor-dependent pathway via the GR. Rg1 stimulation resulted in an increase in the level of -catenin, culminating its nuclear accumulation, and subsequent activation of VEGF expression. Transfection of a stable form of -catenin (S37A) or the use of a glycogen synthase kinase 3 inhibitor to stabilize -catenin induced VEGF synthesis, whereas small interfering RNA-mediated down-regulation of -catenin did not, confirming that the effect was -catenin-specific. Using a luciferase reporter gene assay, we observed that Rg1 increased T-cell factor/lymphoid enhancer factor transcriptional activity. These events were mediated via a PI3K-dependent phosphorylation of the inhibitory Ser⁹ residue of glycogen synthase kinase 3. In addition, the GR antagonist RU486 was able to inhibit Rg1-induced PI3K/Akt and -catenin activation. These findings provide new insights into the mechanism responsible for Rg1 functions.

Received for publication, July 14, 2006 , and in revised form, September 12, 2006.

^* This work was supported by Research Grant Council, Hong Kong SAR Government, Earmarked Research Grants HKBU 2171/03M (to R. N. S. W.) and HKU 7484/04M and HKU 7599/05M (to A. S. T. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Zoology, University of Hong Kong, Hong Kong. Tel.: 852-2299-0865; Fax: 852-2559-9114; E-mail: awong1{at}hku.hk.

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