Stereoisomers ginsenosides-20(S)-Rg3 and -20(R)-Rg3 differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma

Ginsenosides are considered the major constituents that are responsible for most of the pharmacological actions of ginseng. However, some ginsenosides exist as stereoisomeric pairs, detailed and molecular exposition based on the structural differences of ginsenoside stereoisomers has not been emphasized in most studies. Here we explore the functional differences of ginsenoside Rg3 stereoisomers on angiogenesis. In this study, we demonstrated the distinctive differential angiogenic activities of 20(S)-Rg3 and 20(R)-Rg3 stereoisomers. 20(S)-Rg3 at micromolar concentration promotes human endothelial cells proliferation, migration and tube formation in vitro, as well as ex vivo endothelial sprouting. The effects induced by 20(S)-Rg3 are significantly more potent than 20(R)-Rg3. These effects are partially mediated through the activation of AKT/ERK-eNOS signaling pathways. Moreover, knockdown of peroxisome proliferator-activated receptor-gamma (PPARγ) by specific small interference RNA abolished the 20(S)-Rg3-induced angiogenesis, indicating that PPARγ is responsible for mediating the angiogenic activity of Rg3. Using reporter gene assay, the PPARγ agonist activity of 20(S)-Rg3 has been found 10-fold higher than that of 20(R)-Rg3. Computer modeling also revealed the differential binding is due to the chiral center of 20(S)-Rg3 can form a critical hydrogen bond with Tyr473 of PPARγ ligand binding domain. The present study elucidated the differential angiogenic effects of Rg3 stereoisomers by acting as agonist of PPARγ. The results shed light on the structural difference between two ginsenoside stereoisomers that can lead to significant differential physiological outcomes which should be carefully considered in the future development of ginsenoside-based therapeutics.

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