Novel application of paeoniflorin: Stabilization of atherosclerotic plaques via the AMPK/PPARδ signaling pathway.

BACKGROUND: Phenotypic switching of smooth muscle cells is a core event in atherosclerosis, and atherosclerosis is recognized as a smooth muscle cell-driven tumor-like disease. Paeoniflorin (PF), a bioactive monoterpene glycoside isolated from Paeonia lactiflora and Paeonia veitchii, which exerts beneficial effects on both cardiovascular diseases and tumors. However, whether it ameliorates atherosclerosis by mediating the phenotypic switching of VSMC to enhance plaque stability remains unclear. The present study aims to clarify the plaque-stabilizing efficacy of paeoniflorin and unravel its underlying mechanisms.

METHODS: In vitro, tunicamycin induced VSMC to establish a phenotypic switching model. In vivo, ApoE-/- mice were fed a high-fat diet to induce atherosclerosis. Aortic tissue pathological changes were measured by Oil Red O staining, H&E staining, Sirius red staining, Masson staining, immunofluorescence, and fluorescence staining. Western blotting was employed for mechanistic studies.

RESULTS: Our results indicated that PF significantly reduced GRP78 and vimentin expression in VSMC, while increased calponin expression. PF significantly improved cardiac function in ApoE-/- mice, reduced inflammatory factors, oxidative stress, plaque area and necrotic core regions, while increased plaque collagen content and fibrous cap thickness. Furthermore, PF downregulated the expression of aorta GRP78, CHOP, vimentin, osteopontin, KLF4, and MMP2, while upregulated α-SMA and calponin expression. Concurrently, PF activated the AMPK/PPARδ signaling pathway, inhibited GRP78 and vimentin expression, enhanced calponin expression, and improved atherosclerosis.

CONCLUSIONS: This study demonstrated that PF inhibited ER stress-induced VSMC phenotypic switching by activated the AMPK/PPARδ signaling pathway, thus enhanced atherosclerosis plaque stability.