title: Stereoisomers ginsenosides-20(S)-Rg₃ and -20(R)-Rg₃ differentially induce angiogenesis through peroxisome proliferator-activated receptor-gamma.
abstract: 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.
authors.affiliation: Department of Biology, Faculty of Science, Hong Kong Baptist University, Hong Kong.
authors.forename: Hoi-Hin
authors.initials: HH
authors.lastname: Kwok
authors.forename: Guan-Lun
authors.initials: GL
authors.lastname: Guo
authors.forename: Justin Kai-Chi
authors.initials: JK
authors.lastname: Lau
authors.forename: Yuen-Kit
authors.initials: YK
authors.lastname: Cheng
authors.forename: Jiang-Rong
authors.initials: JR
authors.lastname: Wang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Jiang
authors.forename: Man-Hong
authors.initials: MH
authors.lastname: Keung
authors.forename: Nai-Ki
authors.initials: NK
authors.lastname: Mak
authors.forename: Patrick Ying-Kit
authors.initials: PY
authors.lastname: Yue
authors.forename: Ricky Ngok-Shun
authors.initials: RN
authors.lastname: Wong
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000737:chemistry / Q000494:pharmacology*; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D042783:Endothelial Cells / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D017930:Genes, Reporter; D036145:Ginsenosides / Q000737:chemistry / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D015394:Molecular Structure; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: D043925:Angiogenesis Inducing Agents; D036145:Ginsenosides; D047495:PPAR gamma; D034741:RNA, Small Interfering; C097367:ginsenoside Rg3