Ginsenoside Rb1 alleviates atherosclerosis by modulating vascular smooth muscle cell proliferation, foam cell...

Atherosclerosis features chronic inflammation and lipid accumulation; vascular smooth muscle cells (VSMCs) contribute by proliferating and becoming foam cells via oxidized LDL (ox-LDL) uptake through lectin-like ox-LDL receptor-1 (LOX-1).

To test whether ginsenoside Rb1 limits neointima formation and atherosclerosis by inhibiting VSMC proliferation and foam formation via c-JUN/AP-1-dependent regulation of LOX-1, with autophagy as a supportive mechanism.

In vivo carotid ligation models (complete in C57BL/6 J; partial in ApoE-/-) with perivascular Rb1 in F-127 hydrogel, plus in vitro analyses in A7R5 VSMCs.

Lesion burden was quantified histologically. VSMC proliferation (EdU, cell-cycle proteins), lipid accumulation (Oil Red O, BODIPY), intracellular cholesterol, and Dil-ox-LDL uptake were measured. Network pharmacology/docking nominated targets; biotin-Rb1 pull-down validated binding. c-JUN phosphorylation/AP-1 activity, LOX-1 expression, and autophagy markers (LC3-II, p62) were assessed; AP-1 was inhibited with T5224.

Rb1 reduced ligation-induced neointima in C57BL/6 J mice and decreased plaque size and lipid content in ApoE-/- carotids. In VSMCs, Rb1 suppressed proliferation, lowered ox-LDL uptake and total cholesterol, downregulated LOX-1. Network analyses identified JUN among the top Rb1 targets; docking predicted binding and pull-down confirmed direct interaction with c-JUN (and PTGS2). Rb1 decreased c-JUN phosphorylation and AP-1 activity; AP-1 blockade with T5224 recapitulated reductions in LOX-1 and ox-LDL uptake. Rb1 increased LC3-II and decreased p62, consistent with enhanced autophagy.

Rb1 mitigates atherosclerosis by inhibiting VSMC proliferation and foam formation through suppression of c-JUN/AP-1-mediated LOX-1 transcription and activation of autophagy. These actions support Rb1 as a promising phytotherapeutic for plaque attenuation and stabilization.