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.
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.
Leung
Kar Wah
KW
Department of Biology, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China.
Pon
Yuen Lam
YL
Wong
Ricky N S
RN
Wong
Alice S T
AS
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*
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