Posted by Atherosclerosis is a progressive inflammatory disease characterized by the accumulation of lipids in the arterial vessel wall, which begins in early life. The disease develops with the formation of atherosclerotic plaques, leading to narrowing of the arterial lumen. Atherosclerotic plaques often remain stable for years but can rapidly become unstable, rupture, and trigger thrombus formation. Risk factors such as family history, hypercholesterolemia, hypertension, obesity, and cigarette smoking promote the development and progression of the disease. Accordingly, in addition to the restriction of the vessel lumen, the presence of atherosclerotic plaques is associated with an increased risk of acute cardiovascular events, such as myocardial infarction (MI) and stroke. Current therapies reduce the risk of cardiovascular disorders through the treatment of hyperlipidemia, hypertension, and surgical interventions. However, atherosclerotic cardiovascular disease (ASCVD) remains one of the leading causes of death. Additional therapeutic approaches are needed to further reduce the risk of cardiovascular events.
Cells in atherosclerotic plaques undergo subtype transitions and participate in the progression of regulated necrosis, which plays a significant role in atherosclerosis. One of the best-defined forms of regulated necrosis is pyroptosis, a pro-inflammatory form of regulated cell death, characterized by the formation of plasma membrane pores via members of the gasdermin (GSDM) protein family. The subsequent activation step leads to the assembly of the NOD-like receptor protein 3 (NLRP3) inflammasome, which facilitates self-cleavage and activation of caspase-1, accelerates the maturation of interleukin-1ß (IL-1ß) and interleukin-18 (IL-18) precursors, and cleaves GSDMD into its active form, the amino-terminal GSDMD (GSDMD-N). Once activated, GSDMD-N promotes the formation of membrane pores, releases IL-1ß and IL-18, induces DNA degradation, and causes cell swelling5,6.
Recent studies reveal that up to 30–70% of the damaged cells in atherosclerotic lesions originate from vascular smooth muscle cells (VSMCs). Cholesterol accumulation in vascular smooth muscle cells (VSMCs) leads to the formation of lipid-loaded cells, subsequently triggering key events in atherogenesis. Moreover, VSMCs are major mediators of the propagation and perpetuation of inflammation throughout the vessel wall. During the development of atherosclerosis, the accumulation of oxidized low-density lipoprotein (ox-LDL) in the arterial wall leads to the transformation of VSMCs into foam cells. Additionally, ox-LDL accumulation in the plaque promotes VSMC dysfunction, followed by the activation of a pro-inflammatory response. Therefore, targeting cholesterol metabolism and the inflammatory response in VSMCs presents promising strategies for the prevention and treatment of atherosclerosis.
Studies have reported that cyclodextrins have anti-atherosclerotic efficacy through various mechanisms, such as promoting cholesterol efflux from atherosclerotic plaques/macrophages, inhibiting the oxidation of plasma LDL, increasing plasma HDL levels, reducing cholesterol crystal-induced complement activation, and modifying gut flora. However, it remains unclear whether cyclodextrin attenuates atherosclerosis by inhibiting pyroptosis. Therefore, this study aims to investigate whether methyl-ß-cyclodextrin (Mß-CD), a representative cyclodextrin, attenuates GSDMD-mediated pyroptosis in atherosclerotic animal models and ox-LDL-induced VSMCs.
The data suggest that Mß-CD alleviated the inflammatory response and improved cellular viability following GSDMD-mediated pyroptosis in rat VSMCs. A novel mechanism was proposed by which Mß-CD attenuates atherosclerosis by reducing GSDMD-mediated pyroptosis, a key pathogenic factor in atherosclerosis development through the TLR4/NF-κB/NLRP3 pathway. Understanding the molecular mechanisms of pyroptosis and the anti-atherosclerotic effects of Mß-CD provides deeper insight into the pathogenesis of atherosclerosis and offers a potential therapeutic strategy for its treatment.
Sagor, M.I.H., Wang, Q., Wang, J. et al. Cyclodextrin attenuates atherosclerosis by diminishing gasdermin D (GSDMD)-mediated pyroptosis. Sci Rep 15, 21605 (2025). https://doi.org/10.1038/s41598-025-04889-2
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