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

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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.

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.

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Data Availability

The datasets used and-or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

ACTA1:

Actin, alpha 1

BW:

Body weight

CH:

Cardial hypertrophy

CPVT:

Catecholaminergic polymorphic ventricular tachycardia

FDR:

False discovery rate

GO:

Gene ontology

HW:

Heart weight

H&E taining:

Hematoxylin & Eosin staining

HDAC:

Histone deacetylase

IκB:

Inhibitor of NF-κB

LVEDP:

Left ventricular diastolic pressure

LVESP:

Left ventricular systolic pressure

LCC:

L-type calcium channel

MH:

Malignant hyperthermia

mTAC:

Minimally invasive transverse aortic constriction

MEF-2:

Myocyte enhancer factor-2

β-MHC:

Myosin, heavy polypeptide 7, cardiac muscle, and beta

NCX:

Na+-Ca2+exchanger

NPPA:

Natriuretic peptide type A

NPPB:

Natriuretic peptide type B

NRCM:

Neonatal rat cardiomyocyte

NF-κB:

Nuclear factor kappa-B

PE:

Phenylephrine

RyR2:

Ryanodine receptor 2

SERCA2:

Sarcoplasmic reticulum calcium-transporting ATPases 2

TL:

Tibia length

TAC:

Transverse aortic contraction

WGA taining:

Wheat Germ Agglutinin staining

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Acknowledgements

This work was supported by the fund of Natural Science Foundation of China (grant number 81970209). Thanks are also due to Professor Nanthakumar for the valuable discussion.

Funding

This study was supported by the fund of Natural Science Foundation of China (grant number 81970209).

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Authors and Affiliations

  1. Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China

    Yi Gao, Shuai Li, Xueyan Liu, Daoyuan Si, Weiwei Chen, Huan Sun & Ping Yang

  2. Jilin Provincial International Joint Research Center of Cardiovascular Disease Precision Medicine, Changchun, China

    Yi Gao, Xueyan Liu, Daoyuan Si, Weiwei Chen, Huan Sun & Ping Yang

  3. Jilin Provincial Precision Medicine Key Laboratory for Cardiovascular Genetic Diagnosis, Changchun, China

    Yi Gao, Xueyan Liu, Daoyuan Si, Weiwei Chen, Huan Sun & Ping Yang

  4. Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China

    Fenghua Yang

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Correspondence to Huan Sun or Ping Yang.

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Supplementary Information

Supplemental Figure 1.

The expression of eight DEGs in the Treated and Untreated TAC group. The left 2 bars of each figure show the relative gene expression detected by transcriptome sequencing. The right two bars show the gene expression of the same gene verified by qRT-PCR. *P < 0.05, **P < 0.01, ***P < 0.001. (PNG 591 kb)

High resolution image (TIF 25129 kb)

Supplemental Figure 2.

Dose screening test of PE and dantrolene in NRCMs. Cardiomyocytes were treated with various concentrations of PE (0, 1, 10, 50, 100, and 500 μM) for 24 h. (A) The cell viability decreased with an increase in the concentration of PE. B. The expression of hypertrophy markers increased with an increase in PE concentration. (C-E) The PE intervention myocardial hypertrophy group was treated with 50 μM PE. In addition to PE, the dantrolene intervention group was treated with 0, 1, 10, 50, 100, and 500 μM of dantrolene for 24 h. Cell viability (C) and quantitative protein for hypertrophy marker BNP (D, E) were detected to determine the dantrolene concentration. *compared with the control group, P < 0.05, **compared with the control group, P < 0.01, ***compared with the control group, P < 0.001. #compared with the PE group, P < 0.05，##compared with the control group, P < 0.01, ### compared with the control group, P < 0.001. (PNG 458 kb)

High resolution image (TIF 7664 kb)

Supplemental Figure 3.

The effects of dantrolene on PE-induced hypertrophy in NRCMs. The changes in protein expression related to calcineurin/NFAT3 pathways in NRCMs under the effect of dantrolene, FK506 or CnA overexpression. **compared with the control group, P < 0.01, ***compared with the control group, P < 0.001. ## compared with the PE control group, P < 0.01, ###compared with the PE control group, P < 0.001. △△compared with the PE + dantrolene group, P < 0.01, △△△compared with the PE+ dantrolene group, P < 0.001. (PNG 484 kb)

High resolution image (TIF 54817 kb)

Supplemental Table 1

(DOCX 29 kb)

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Gao, Y., Li, S., Liu, X. et al. RyR2 Stabilizer Attenuates Cardiac Hypertrophy by Downregulating TNF-α/NF-κB/NLRP3 Signaling Pathway through Inhibiting Calcineurin. J. of Cardiovasc. Trans. Res. (2024). https://doi.org/10.1007/s12265-023-10376-8

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