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Cardiac-specific deletion of BRG1 ameliorates ventricular arrhythmia in mice with myocardial infarction

Acta Pharmacologica Sinica volume 45, pages 517–530 (2024)Cite this article

Abstract

Malignant ventricular arrhythmia (VA) after myocardial infarction (MI) is mainly caused by myocardial electrophysiological remodeling. Brahma-related gene 1 (BRG1) is an ATPase catalytic subunit that belongs to a family of chromatin remodeling complexes called Switch/Sucrose Non-Fermentable Chromatin (SWI/SNF). BRG1 has been reported as a molecular chaperone, interacting with various transcription factors or proteins to regulate transcription in cardiac diseases. In this study, we investigated the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. Myocardial infarction (MI) mice were established by ligating the left anterior descending (LAD) coronary artery, and electrocardiogram (ECG) was monitored. Epicardial conduction of MI mouse heart was characterized in Langendorff-perfused hearts using epicardial optical voltage mapping. Patch-clamping analysis was conducted in single ventricular cardiomyocytes isolated from the mice. We showed that BRG1 expression in the border zone was progressively increased in the first week following MI. Cardiac-specific deletion of BRG1 by tail vein injection of AAV9-BRG1-shRNA significantly ameliorated susceptibility to electrical-induced VA and shortened QTc intervals in MI mice. BRG1 knockdown significantly enhanced conduction velocity (CV) and reversed the prolonged action potential duration in MI mouse heart. Moreover, BRG1 knockdown improved the decreased densities of Na+ current (INa) and transient outward potassium current (Ito), as well as the expression of Nav1.5 and Kv4.3 in the border zone of MI mouse hearts and in hypoxia-treated neonatal mouse ventricular cardiomyocytes. We revealed that MI increased the binding among BRG1, T-cell factor 4 (TCF4) and β-catenin, forming a transcription complex, which suppressed the transcription activity of SCN5A and KCND3, thereby influencing the incidence of VA post-MI.

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Fig. 1: BRG1 was upregulated after MI.
Fig. 2: BRG1 knockdown reduced the incidence of VAs after MI.
Fig. 3: BRG1 knockdown affected the CV and the AP duration after MI.
Fig. 4: BRG1 knockdown affected the APD, INa and Ito in cardiomyocytes of MI mice.
Fig. 5: BRG1 knockdown affected the protein and mRNA levels of Nav1.5 and Kv4.3 in MI mouse hearts.
Fig. 6: BRG1 inhibition prevented hypoxia-induced reductions in SCN5A/Nav1.5/INa and KCND3/Kv4.3/Ito in NMVCs.
Fig. 7: BRG1, β-catenin and TCF4 formed a complex in myocardial nuclei post-MI.
Fig. 8: BRG1/β-catenin/TCF4-mediated transcriptional suppression of Nav1.5 and Kv4.3 channels.
Fig. 9: Schematic diagram depicting the role of BRG1 in VA after MI.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872870, 82373868 and 82070312), Scientific Fund of Heilongjiang Province (LH2022H003), Scientific research project of Provincial Scientific Research Institute of Heilongjiang Province (CZKYF2022-1-B007), Heilongjiang Province Postdoctoral Foundation (LBH-Q19155), and Excellent Youth Fund of School of Pharmacy, Harbin Medical University (2019-YQ-01, 2020-YQ-02).

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  1. These authors contributed equally: Jing Li, Zi-yue Ma

Authors and Affiliations

  1. Department of Pharmacology, College of Pharmacy, Harbin Medical University, Baojian Road, Nangang District, Harbin, 150081, China

    Jing Li, Zi-yue Ma, Yun-feng Cui, Ying-tao Cui, Xian-hui Dong, Yong-zhen Wang, Yu-yang Fu, Ya-dong Xue, Ting-ting Tong, Ying-zi Ding, Ya-mei Zhu, Hai-jun Huang, Ling Zhao, Hong-zhao Lv, Ling-zhao Xiong, Kai Zhang, Yu-xuan Han, Tao Ban & Rong Huo

  2. Heilongjiang Academy of Medical Sciences, Baojian Road, Nangang District, Harbin, 150081, China

    Tao Ban

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Contributions

RH and TB designed the experiments and supervised the project; JL and ZYM were responsible for manuscript writing, performed the experiments, analyzed the data, and prepared figures and table; YFC, YTC, XHD, YZD, YDX and YZW performed the experiments and revised the manuscript; TTT, HJH and XHD performed the experiments and approved the final draft; YYF, YMZ, YDX, TTT and HJH prepared the figures and tables; LZX, HZL, LZ, KZ, and YXH performed the statistical analysis.

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Correspondence to Tao Ban or Rong Huo.

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The authors declare no competing interests.

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All experiments were in line with the NIH guidelines (Guide for the care and use of laboratory animals, NIH Publication No. 85-23, revised 1996) and approved by the Animal Experimental Ethics Committee of Pharmaceutical College, Harbin Medical University (Approval no. IRB3102619).

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Li, J., Ma, Zy., Cui, Yf. et al. Cardiac-specific deletion of BRG1 ameliorates ventricular arrhythmia in mice with myocardial infarction. Acta Pharmacol Sin 45, 517–530 (2024). https://doi.org/10.1038/s41401-023-01170-y

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