MgCl2 Attenuates ox-LDL-Induced Vascular Smooth Muscle-Derived Foam Cells Pyroptosis by Downregulating the TLR4/NF-κB Signaling Pathway.

Abstract

Pyroptosis is a type of programmed cell death that is generally upregulated during atherosclerosis (AS). Magnesium, an important cation in the body, has exhibited an antiatherosclerotic effect. We collected AS model datasets from the Gene Expression Omnibus (GEO) and explored the correlation between pyroptosis and AS through a series of bioinformatics methods. We next investigated the impact of oxidized low-density lipoprotein (ox-LDL) on primary cultured vascular smooth muscle cells (VSMCs) foaminess and pyroptosis. Finally, foam cells were preconditioned with different concentrations of MgCl2 to explore its influence on ox-LDL-induced VSMCs pyroptosis. NLRP3-mediated pyroptosis plays a core role in regulating AS progression as shown by bioinformatic analysis. Ox-LDL (50/75/100mg/L) increased CE/TE ratio (> 50%) in VSMCs and prompted VSMC-derived foam cell formation, and (75/100mg/L) ox-LDL-induced pyroptosis. Compared to 1mmol/L MgCl2, 10mmol/L MgCl2 significantly downregulated the expression of pyroptosis related molecules in VSMCs induced by 75mg/L ox-LDL, including NLRP3, ASC, caspase-1, and GSDMD. The secretion of IL-1β, IL-18, and LDH was also inhibited by MgCl2. According to CCK-8 and Hoechst 33,342/PI staining, the damage to VSMCs viability induced by ox-LDL was ameliorated by MgCl2. In addition, MgCl2 attenuated the upregulation of TLR4, IKKβ, and p65 and the downregulation of IκBα in VSMCs induced by ox-LDL. The present study demonstrated that pyroptosis-related genes were the core genes in AS. We also revealed the effect and underlying mechanism of MgCl2 on ox-LDL-induced VSMCs pyroptosis, suggesting that MgCl2 has promising clinical applications for AS pyroptosis prevention and treatment.