SXBX pill suppresses homocysteine-induced vascular smooth muscle cells dedifferentiation by inhibiting NLRP3 inflammasomes activation via ERK/p38 MAPK pathways

The dedifferentiation of vascular smooth muscle cells (VSMCs) is a key event in the pathogenesis of vascular remodeling-related disease. The present study aimed to investigate the effects of shexiangbaoxin (SXBX) pill, a traditional Chinese medicinal formula on VSMCs dedifferentiation and its potential mechanisms. High-fat diet (HFD) was introduced to lipoprotein receptor-deficient (LDLR^-/-) mice to generate hyperhomocysteinemia (HHcy), and plasma Hcy and lipid levels were analyzed. The phenotype of VSMCs was assessed in mice with the treatment of low (45 mg/kg/d) or high (90 mg/kg/d) SXBX pill by measuring the contractile protein α-SMA, SM22α and synthetic proteins OPN using RT-qPCR, western blotting and immunofluorescence assay. In vitro, the proliferation, migration and dedifferentiation of VSMCs were measured by MTT, Edu incorporation, wound healing and western blotting assay. Small interfering RNA technology was used to examine the role of NLRP3 in the effects of SXBX pill on dedifferentiation. The results indicated that although SXBX pill had no influence on HFD-induced HHcy and hyperlipidaemia, it reversed HHcy-induced dedifferentiation of VSMCs in vivo. SXBX pill significantly inhibited proliferation, migration and dedifferentiation of Hcy-treated VSMCs. In addition, we found that Hcy activated NLRP3 inflammasomes in VSMCs and SXBX pill could attenuate NLRP3 inflammasomes activation. Moreover, subsequent analysis suggested that SXBX pill inhibited NLRP3 inflammasomes activation through regulation of ERK1/2 and p38 MAPK pathway. Knockdown of NLRP3 reversed the inhibitory effects of SXBX pill in VSMCs. In conclusion, SXBX pill inhibited Hcy-induced proliferation, migration and dedifferentiation of VSMCs by suppressing NLRP3 inflammasomes activation via of ERK/p38 MAPK pathway.