RyR2 inhibitor attenuates cardiac hypertrophy by downregulating TNF-α/NF-κB/NLRP3 signaling pathway

Background: Cardiac Ryanodine receptors (RyR2) can regulate Ca2+ release in the excitation-contraction coupling, when activated, it releases a large amount of Ca2+ into the cytoplasm. Additionally, studies have shown that dantrolene (a RyR2 inhibitor) protects against heart failure and arrhythmias by inhibiting domain decompression, Ca2+ leakage and diastolic Ca2+ sparking. However, the role and mechanism of dantrolene in cardiac hypertrophy remain unclear. Objective: In this study, we aimed to evaluate the therapeutic effects of dantrolene on pressure overload-induced cardiac hypertrophy in mice models by transverse aortic contraction (TAC) surgery and to explore its potential mechanism. Methods: C57/B6 mice (age: 8 weeks) underwent TAC or sham surgical procedure and were administered oral dantrolene (30 mg/kg) or the solvent drug postoperatively. After 4 weeks of drug treatment, RNA sequencing of mice left ventricle was performed.qRT–PCR validation was performed using SYBR Green assays. Results: We found that dantrolene significantly alleviated TAC-induced cardiac hypertrophy. According to RNA sequencing, 184 down-regulated genes were found after dantrolene treatment compared with TAC group, 8 of these were validated with qRT–PCR. According to the KEGG analysis, Creb3l3, IL18R1 and Ccl5 were down-regulated after dantrolene treatment, which were related to TNF-α pathway. Conclusion: As a RyR2 inhibitor, dantrolene attenuates cardiac hypetrophy through downregulating the TNF-α/NF-κB/NLRP3 signaling pathway. transcrptional analysis of dantrolene on pressure overload induced hypetrophy.