Signaling pathway of ginsenoside‐Rg1 leading to nitric oxide production in endothelial cells

Abstract

We here provide definitive evidence that ginsenosideRg1, the pharmacologically active component of ginseng, is a functional ligand of the glucocorticoid receptor (GR) as determined by fluorescence polarization assay. Rg1 increased the phosphorylation of GR, phosphatidylinositol-3 kinase (PI3K), Akt/PKB and endothelial nitric oxide synthase (eNOS) leading to increase nitric oxide (NO) production in human umbilical vein endothelial cell. Rg1-induced eNOS phosphorylation and NO production were significantly reduced by RU486, LY294,002, or SH-6. Also, knockdown of GR completely eliminated the Rg1-induced NO production. This study revealed that Rg1 can indeed serve as an agonist ligand for GR and the activated GR can induce rapid NO production from eNOS via the non-transcriptional PI3K/Akt pathway.

Ginsenoside Rg1, a Novel Glucocorticoid Receptor Agonist of Plant Origin, Maintains Glucocorticoid Efficacy with Reduced Side Effects

“…GR nuclear translocation is required for the physiological and pharmacological functions of GCs. Although no direct evidence for Rg1 binding to GR was reported in this study, our results clearly demonstrate that Rg1 induces nuclear translocation of GR in RAW264.7 and A549 cells, in accordance with previous studies that report Rg1 to be a functional ligand of GR in which a reporter gene and competitive binding methods were used (34)(35)(36).…”

“…Even though Rg1 was reported as a functional ligand of GR (34)(35)(36) and demonstrated to drive GR into nucleus, it seems that Rg1 exhibits an altered gene regulation profile, able to affect only a subset of the genes normally regulated by GCs. Our results in this study demonstrate that Rg1 does not impair proliferation or differentiation of osteoblasts, as is the case with DEX.…”

“…Among the ginsenosides, Rg1 is the most abundant and is the active ingredient of P. ginseng (32,33). Previous studies have shown Rg1 to be a functional ligand of GR (34)(35)(36). Furthermore, Rg1 inhibits LPS-stimulated cytokine production in vitro, indicating that Rg1 may exerts anti-inflammatory effects via GR (37,38).…”

Korean Red Ginseng Improves Vascular Stiffness in Patients with Coronary Artery Disease

“…The ginsenoside PPT protects endothelial cells from hydrogen peroxide-induced cell injury and death by ameliorating oxidative stress [27]. In addition, ginsenoside Rg1 functions as an agonist at the glucocorticoid receptor, leading to the production of NO by eNOS via the non-transcriptional PI3K/Akt pathway [28]. KRG also inhibits hydrogen peroxide-induced cell death by decreasing the expression of the pro-apoptotic protein caspase-3 and the pro-inflammatory protein cyclooxygenase 2, and increasing the expression of the anti-apoptotic protein Bcl-2 [2].…”

“…PWV is also affected by endothelial function and is regulated by endothelium-derived NO and hyperpolarizing factor [25,26]. KRG has probable anti-oxidative properties; it is known to promote NO production and to protect endothelial cells from oxidative stress [2,15,27,28]. The ginsenoside PPT protects endothelial cells from hydrogen peroxide-induced cell injury and death by ameliorating oxidative stress [27].…”