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.

Graphical Abstract

Schematic diagram of the mechanism of Dantrolene. Dantrolene attenuates cardiac hypertrophy through inhibition of TNF-α/NF-κB/NLRP3 pathway by downregulating Calcineurin/NFAT3 pathway.

中文翻译：

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RyR2 稳定剂通过抑制钙调磷酸酶下调 TNF-α/NF-κB/NLRP3 信号通路，从而减轻心脏肥大

Ryanodine 受体 2 (RyR2) 及其稳定剂对心脏肥大的作用尚不清楚。接受横向主动脉收缩 (TAC) 或假手术的 C57/BL6 小鼠接受丹曲林、RyR2 稳定剂或对照药物。 Dantrolene 显着减轻了 TAC 诱导的小鼠心脏肥大，并且进行的 RNA 测序表明钙调神经磷酸酶/NFAT3 和 TNF-α/NF-κB/NLRP3 是关键信号通路。心脏组织和新生大鼠心肌细胞（NRCM）模型的进一步表达分析和Western blot证实丹曲林降低了钙调神经磷酸酶/NFAT3信号通路和TNF-α/NF-κB/NLRP3信号通路的激活，这与FK506相似，可能是钙调神经磷酸酶过度表达会减弱。本研究首次表明，RyR2 稳定剂丹曲林通过抑制钙调神经磷酸酶来减轻心脏肥大，从而下调 TNF-α/NF-κB/NLRP3 通路。

图形概要

丹曲林的作用机制示意图。 Dantrolene 通过下调 Calcineurin/NFAT3 通路抑制 TNF-α/NF-κB/NLRP3 通路，从而减轻心脏肥大。