Dietary
saponins have the potential to ameliorate atherosclerosis
(AS). Gypenosides of Gynostemma pentaphyllum (GPs)
have been used as functional foods to exhibit antiatherosclerotic
activity. The present study aimed to explore the protective effect,
underlying mechanism and active substances of GPs on AS in
vivo and in vitro. Results demonstrated
GPs administration reduced the serum concentrations of TC and LDL-C,
upregulated the plasma HDL-C content, inhibited the secretion of ICAM-1,
VCAM-1, and MCP-1, and alleviated vascular lesions in VitD3 plus high cholesterol diet-induced AS rats as well as reduced adhesion
factors levels in ox-LDL-stimulated HUVECs, which was potentially
associated with suppressing PCSK9/LOX-1 pathway. Further activity-guided
phytochemical investigation of GPs led to the identification of five
new dammarane-type glycosides (1–5) and ten known analogs (6–15).
Bioassay evaluation showed compounds 1, 6, 7, 12, 13, and 14 observably reduced the expressions of PCSK9 and LOX-1, as well as
the secretion of adhesion factors in injured HUVECs. Molecular docking
experiments suggested that the active saponins of GPs might bind to
the allosteric pocket of PCSK9 located at the catalytic and C-terminal
domains, and 2α–OH-protopanaxadiol-type gypenosides might
exert a higher affinity for an allosteric binding site on PCSK9 by
hydrogen-bond interaction with ARG-458. These findings provide new
insights into the potential nutraceutical application of GPs and their
bioactive compounds in the prevention and discovery of novel therapeutic
strategies for AS.
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