Gypenoside XVII Prevents Atherosclerosis by Attenuating Endothelial Apoptosis and Oxidative Stress: Insight into the ERα-Mediated PI3K/Akt Pathway

Int J Mol Sci. 2017 Feb 9;18(2):77. doi: 10.3390/ijms18020077.


Phytoestrogens are estrogen-like compounds of plant origin. The pharmacological activities of phytoestrogens are predominantly due to their antioxidant, anti-inflammatory and lipid-lowering properties, which are mediated via the estrogen receptors (ERs): estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) and possibly G protein-coupled estrogen receptor 1 (GPER). Gypenoside XVII (GP-17) is a phytoestrogen that is widely used to prevent cardiovascular disease, including atherosclerosis, but the mechanism underlying these therapeutic effects is largely unclear. This study aimed to assess the anti-atherogenic effects of GP-17 and its mechanisms in vivo and in vitro. In vivo experiments showed that GP-17 significantly decreased blood lipid levels, increased the expression of antioxidant enzymes and decreased atherosclerotic lesion size in ApoE-/- mice. In vitro experiments showed that GP-17 significantly prevented oxidized low-density lipoprotein (Ox-LDL)-induced endothelial injury. The underlying protective mechanisms of GP-17 were mediated by restoring the normal redox state, up-regulating of the ratio of Bcl-2 to Bax and inhibiting the expression of cleaved caspase-3 in Ox-LDL-induced human umbilical vein endothelial cell (HUVEC) injury. Notably, we found that GP-17 treatment predominantly up-regulated the expression of ERα but not ERβ. However, similar to estrogen, the protective effect of GP-17 could be blocked by the ER antagonist ICI182780 and the phosphatidylinositol 3-kinase (PI3K) antagonist LY294002. Taken together, these results suggest that, due to its antioxidant properties, GP-17 could alleviate atherosclerosis via the ERα-mediated PI3K/Akt pathway.

Keywords: apoptosis; atherosclerosis; estrogen receptors; gypenoside XVII; oxidative damage.

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apoptosis / drug effects*
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Caspase 3 / metabolism
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism*
  • Estrogen Receptor alpha / genetics
  • Estrogen Receptor alpha / metabolism
  • Gene Expression Regulation
  • Gynostemma / chemistry
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Lipid Metabolism
  • Lipoproteins, LDL / metabolism
  • Lipoproteins, LDL / pharmacology
  • Mice
  • Mice, Knockout
  • Molecular Structure
  • Oxidative Stress / drug effects*
  • Phosphatidylinositol 3-Kinase / metabolism
  • Plant Extracts / chemistry
  • Plant Extracts / pharmacology
  • Protective Agents / pharmacology
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects


  • Apolipoproteins E
  • Estrogen Receptor alpha
  • Lipoproteins, LDL
  • Plant Extracts
  • Protective Agents
  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Oxygen Species
  • gypenoside
  • oxidized low density lipoprotein
  • Phosphatidylinositol 3-Kinase
  • Proto-Oncogene Proteins c-akt
  • Caspase 3