RyR2 Stabilizer Attenuates Cardiac Hypertrophy by Downregulating TNF-α/NF-κB/NLRP3 Signaling Pathway through Inhibiting Calcineurin,Journal of Cardiovascular Translational Research

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RyR2 Stabilizer Attenuates Cardiac Hypertrophy by Downregulating TNF-α/NF-κB/NLRP3 Signaling Pathway through Inhibiting Calcineurin
Journal of Cardiovascular Translational Research ( IF 2.4 ) Pub Date : 2024-04-23 , DOI: 10.1007/s12265-023-10376-8
Yi Gao _{1,

2,

3} , Shuai Li ₁ , Xueyan Liu _{1,

2,

3} , Daoyuan Si _{1,

2,

3} , Weiwei Chen _{1,

2,

3} , Fenghua Yang ₄ , Huan Sun _{1,

2,

3} , Ping Yang _{1,

2,

3}

Affiliation

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：

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

兰尼碱受体 2 （RyR2）及其稳定剂对心脏肥大的影响尚不清楚。C57/BL6 小鼠接受横主动脉收缩（TAC）或假手术，给予丹曲林、RyR2 稳定剂或对照药物。丹曲林显著减轻 TAC 诱导的小鼠心脏肥大，进行 RNA 测序表明钙调磷酸酶/NFAT3 和 TNF-α/NF-κB/NLRP3 是关键信号通路。进一步的表达分析和心脏组织 Western blot 以及新生大鼠心肌细胞（NRCM）模型证实丹曲林降低钙调磷酸酶/NFAT3 信号通路和 TNF-α/NF-κB/NLRP3 信号通路的激活，这与 FK506 相似，可能会因钙调磷酸酶过表达而减弱。本研究首次表明，RyR2 稳定剂丹曲林通过抑制钙调磷酸酶来减轻心脏肥大，从而下调 TNF-α/NF-κB/NLRP3 通路。