Cyclodextrin attenuates atherosclerosis by diminishing gasdermin D (GSDMD)-mediated pyroptosis

Pyroptosis, a programmed form of cell death, typically increases during the atherosclerosis development. Cyclodextrins are oligosaccharides with anti-atherosclerotic properties. Therefore, the present study aims to explore the role of methyl-ß-cyclodextrin (Mß-CD), a representative of cyclodextrin, in suppressing the development of atherosclerosis. Atherosclerosis animal and cell models were established by feeding ApoE^-/- mice a high-fat diet for 12 weeks and by inducing oxidized low-density lipoprotein (ox-LDL) (75 µg/mL for 24 h) in rat vascular smooth muscle cells (VSMCs), respectively. Meanwhile, Mß-CD (2.0 g/kg, twice a week in vivo and 5mM in vitro) was used to manipulate GSDMD-mediated pyroptosis.The present study revealed a reduction in atherosclerotic plaques in the aorta (19.46 ± 2.38% vs. 8.10 ± 1.28%,P < 0.01), accompanied by a decrease in the number of CD68⁺ cells in the aortic sinus of atherosclerotic mice following Mß-CD intervention. Additionally, there were reduced levels of lipids and cholesterol, as well as lower levels of IL-1ß and IL-18 cytokines, alongside decreased activation of the TLR4/NF-κB/NLRP3 pathway. This resulted in decreased pyroptosis proteins in both in vivo (GSDMD-NT: 1.06 ± 0.24 vs. 0.26 ± 0.03, P < 0.01) and in vitro (GSDMD-NT: 1.37 ± 0.15 vs. 0.62 ± 0.14, P < 0.01) models after Mß-CD treatment. Moreover, the number of PI-positive cells was reduced in the atherosclerotic cell model after treatment with Mß-CD. This study provides evidence that Mß-CD may reduce atherosclerosis by inhibiting the TLR4/NF-κB/NLRP3 pathway and GSDMD-mediated pyroptosis, highlighting the need for further investigation of Mß-CD as a potential treatment option for atherosclerosis.