Anti-atherosclerotic role of microRNA-218-5p via regulating the TNFRSF11A/NF-κB/NLRP3/caspase-1 pyroptosis pathway

Atherosclerosis (AS) is linked to many cardiovascular disorders. We investigated the potential roles and mechanisms of microRNA (miR)-218-5p in AS. Primary mouse aortic endothelial cells (MAECs) were induced with ox-LDL, followed by various interventions including miR/gene overexpression and knockdown. An AS mouse model was established in ApoE^-/- mice and treated with miR-218-5p agomir. Serum lipid, inflammatory factor, interleukin (IL)-1β, IL-18, and pyroptosis-related protein levels as well as plasma anti-inflammatory IL-10 and TGF-β levels were determined. The results demonstrated that miR-218-5p overexpression decreased tumor necrosis factor receptor superfamily member 11 A (TNFRSF11A) protein level and ameliorated ox-LDL-induced MAEC pyroptosis. Furthermore, miR-218-5p impeded the nuclear factor (NF)-κB signaling and inactivated NOD-like receptor protein 3 (NLRP3)/caspase-1 via TNFRSF11A. NLRP3 activation partially reversed the impacts of miR-218-5p on pyroptosis. We observed augmented levels of serum total cholesterol, triglyceride, low-density lipoprotein cholesterol, and pro-inflammatory proteins, elevated levels of N-terminus of gasdermin D, TNFRSF11A, nuclear NF-kB p65, phosphorylated p65, NLRP3, and cleaved-caspase-1 proteins in aortic tissue, and reduced serum high-density lipoprotein cholesterol level and cytoplasmic NF-kB p65 protein level in AS-rendered mice. miR-218-5p agomir treatment reduced cell pyroptosis in aorta of AS model mice and improved AS. Briefly, miR-218-5p repressed TNFRSF11A, repressed the NF-κB signaling, and disrupted NLRP3/caspase-1 activation, thereby alleviating pyroptosis and contributing to the improvement of AS.