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 Rg 3 stereoisomers on angiogenesis. In this study, we demonstrated the distinctive differential angiogenic activities of 20(S)-Rg 3 and 20(R)-Rg 3 stereoisomers. 20(S)-Rg 3 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)-Rg 3 are significantly more potent than 20(R)-Rg 3. 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)-Rg 3-induced angiogenesis, indicating that PPARγ is responsible for mediating the angiogenic activity of Rg 3. Using reporter gene assay, the PPARγ agonist activity of 20(S)-Rg 3 has been found 10-fold higher than that of 20(R)-Rg 3. Computer modeling also revealed the differential binding is due to the chiral center of 20(S)-Rg 3 can form a critical hydrogen bond with Tyr473 of PPARγ ligand binding domain. The present study elucidated the differential angiogenic effects of Rg 3 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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