RyR2 Stabilizer Attenuates Cardiac Hypertrophy by Downregulating TNF-α/NF-κB/NLRP3 Signaling Pathway through Inhibiting Calcineurin.

Abstract

The effect of Ryanodine receptor2 (RyR2) and its stabilizer on cardiac hypertrophy is not well known. C57/BL6 mice underwent transverse aortic contraction (TAC) or sham surgery were administered dantrolene, the RyR2 stabilizer, or control drug. Dantrolene significantly alleviated TAC-induced cardiac hypertrophy in mice, and RNA sequencing was performed implying calcineurin/NFAT3 and TNF-α/NF-κB/NLRP3 as critical signaling pathways. Further expression analysis and Western blot with heart tissue as well as neonatal rat cardiomyocyte (NRCM) model confirmed dantrolene decreases the activation of calcineurin/NFAT3 signaling pathway and TNF-α/NF-κB/NLRP3 signaling pathway, which was similar to FK506 and might be attenuated by calcineurin overexpression. The present study shows for the first time that RyR2 stabilizer dantrolene attenuates cardiac hypertrophy by inhibiting the calcineurin, therefore downregulating the TNF-α/NF-κB/NLRP3 pathway.