title: Ginsenoside-Rg1 induces vascular endothelial growth factor expression through the glucocorticoid receptor-related phosphatidylinositol 3-kinase/Akt and beta-catenin/T-cell factor-dependent pathway in human endothelial cells.
abstract: 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 beta-catenin/T-cell factor-dependent pathway via the GR. Rg1 stimulation resulted in an increase in the level of beta-catenin, culminating its nuclear accumulation, and subsequent activation of VEGF expression. Transfection of a stable form of beta-catenin (S37A) or the use of a glycogen synthase kinase 3beta inhibitor to stabilize beta-catenin induced VEGF synthesis, whereas small interfering RNA-mediated down-regulation of beta-catenin did not, confirming that the effect was beta-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 3beta. In addition, the GR antagonist RU486 was able to inhibit Rg1-induced PI3K/Akt and beta-catenin activation. These findings provide new insights into the mechanism responsible for Rg1 functions.
authors.affiliation: Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
authors.forename: Kar Wah
authors.initials: KW
authors.lastname: Leung
authors.forename: Yuen Lam
authors.initials: YL
authors.lastname: Pon
authors.forename: Ricky N S
authors.initials: RN
authors.lastname: Wong
authors.forename: Alice S T
authors.initials: AS
authors.lastname: Wong
mesh_terms: D000818:Animals; D002491:Central Nervous System Agents / Q000494:pharmacology*; D042783:Endothelial Cells / Q000166:cytology* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D004789:Enzyme Activation; D036145:Ginsenosides / Q000494:pharmacology*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D051820:TCF Transcription Factors / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D002491:Central Nervous System Agents; D036145:Ginsenosides; D034741:RNA, Small Interfering; D011965:Receptors, Glucocorticoid; D051820:TCF Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; C035054:ginsenoside Rg1