Ginsenoside-Rg1 Induces Vascular Endothelial Growth Factor Expression through the Glucocorticoid Receptor-related Phosphatidylinositol 3-Kinase/Akt and β-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 ␤-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 Ser 9 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.

Ginsenoside Rg1 ameliorates oxidative stress and myocardial apoptosis in streptozotocin-induced diabetic rats

“…It has been suggested that the PI3K/Akt pathway is important for insulin signal transduction, cell cycle, cell growth, and survival regulation in DM (Matsui and Davidoff, 2007), and activation of the PI3K/Akt pathway is considered protective against the development of diabetic cardiomyopathy. Indeed, many previous studies have shown that treatment with Rg1 was associated with the activation of the PI3K/Akt pathway in human endothelial cells (Leung et al, 2006), hippocampal neuronal cells (Shi et al, 2012), and macrophages (Wang et al, 2014). However, a recent study indicated that Rg1 may protect chondrocyte from interleukin-1β-induced apoptosis via inhibiting the phosphorylation of Akt (Huang et al, 2014).…”

Ginsenoside Rg1 promotes endothelial progenitor cell migration and proliferation

“…Over-expression of VEGF and its receptors promotes blood vessel formation, and VEGF inhibition blocks angiogenesis [31] . Leung KW et al showed that ginsenoside Rg1 promoted the synthesis of VEGF and hence angiogenic activity by activating the PI3K/Akt pathway [32] . Ginsenoside Rg1 could enhance nitric oxide production and the expression of eNOS mRNA in TNF-alpha stimulated HUVECs [33] .…”

Ginsenoside Rg1 promotes bone marrow stromal cells proliferation via the activation of the estrogen receptor-mediated signaling pathway1

“…Ginsenosides are amphiphilic in nature and have the ability to intercalate into the plasma membrane. There is evidence suggesting that ginsenosides interact directly with specific membrane proteins [14,15] . Moreover, like steroid hormones, Rg1 has previously been shown to interact with the glucocorticoid receptor and initiate genomic effects [16,17] .…”