Context-dependent vascular effects of platycodin D: inhibition of neointima formation but aggravation of atherosclerosis with involvement of mTORC1 signaling.

Platycodin D (PD), a triterpenoid saponin from Platycodon grandiflorus, has been reported to have cardiovascular activity, but its actions in vascular smooth muscle cells (VSMCs) and atherosclerosis remain unclear. We integrated network pharmacology, molecular docking, 100-ns molecular dynamics simulation, VSMC assays, and two mouse carotid models. In VSMCs cultured under basal conditions, PD reduced viability and BrdU incorporation, downregulated cyclin D1/E1, and induced TUNEL positivity and cleaved caspase-3. At the cellular level, PD activated mTORC1-associated signaling, increased p70S6K and eIF2α phosphorylation, increased ATF4 protein and activated ATF6, impaired autophagic flux, and induced CHOP-associated endoplasmic reticulum stress. Rapamycin and 4-phenylbutyric acid attenuated PD-induced apoptosis, whereas MHY1485 and thapsigargin exacerbated it. Perivascular PD reduced neointimal hyperplasia after complete carotid ligation in C57BL/6J mice. In contrast, PD accelerated early carotid atherosclerosis after partial ligation in ApoE-/- mice fed a high-fat diet. Under ox-LDL challenge, PD increased VSMC lipid accumulation, Olr1/Cd36 expression, mTORC1-p70S6K signaling, and BrdU incorporation; rapamycin limited these effects. These findings suggest that PD activates an mTORC1-associated stress program whose vascular outcome depends on lipid and flow context. PD may have local anti-neointimal potential but warrants caution in hyperlipidemic atherosclerosis.