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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig1_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig2_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig3_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig4_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig5_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig6_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig7_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig8_HTML.png)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1038%2Fs41401-023-01170-y/MediaObjects/41401_2023_1170_Fig9_HTML.png)
Similar content being viewed by others
References
De Rosa F, Boncompagni F, Calvelli A, Paci A, Guzzo D, Fascetti F, et al. [Ventricular arrhythmias in the acute phase of myocardial infarct and in the postinfarct. A 1-year follow-up]. G Ital Cardiol. 1990;20:607–14.
Wasson S, Reddy HK, Dohrmann ML. Current perspectives of electrical remodeling and its therapeutic implications. J Cardiovasc Pharmacol Ther. 2004;9:129–44.
Liu M, Liu H, Parthiban P, Kang GJ, Shi G, Feng F, et al. Inhibition of the unfolded protein response reduces arrhythmia risk after myocardial infarction. J Clin Invest. 2021;131:e147836.
Kang GJ, Xie A, Liu H, Dudley SC, Jr. MIR448 antagomir reduces arrhythmic risk after myocardial infarction by upregulating the cardiac sodium channel. JCI Insight. 2020;5:e140759.
Ufret-Vincenty CA, Baro DJ, Lederer WJ, Rockman HA, Quinones LE, Santana LF. Role of sodium channel deglycosylation in the genesis of cardiac arrhythmias in heart failure. J Biol Chem. 2001;276:28197–203.
Spitzer KW, Pollard AE, Yang L, Zaniboni M, Cordeiro JM, Huelsing DJ. Cell-to-cell electrical interactions during early and late repolarization. J Cardiovasc Electrophysiol. 2006;17:S8–14.
Zhong Y, Cao P, Tong C, Li X. Effect of ramipril on the electrophysiological characteristics of ventricular myocardium after myocardial infarction in rabbits. J Cardiovasc Med. 2012;13:313–8.
Ando M, Katare RG, Kakinuma Y, Zhang D, Yamasaki F, Muramoto K, et al. Efferent vagal nerve stimulation protects heart against ischemia-induced arrhythmias by preserving connexin43 protein. Circulation. 2005;112:164–70.
Rutledge CA, Ng FS, Sulkin MS, Greener ID, Sergeyenko AM, Liu H, et al. c-Src kinase inhibition reduces arrhythmia inducibility and connexin43 dysregulation after myocardial infarction. J Am Coll Cardiol. 2014;63:928–34.
Xiao C, Gao L, Hou Y, Xu C, Chang N, Wang F, et al. Chromatin-remodelling factor Brg1 regulates myocardial proliferation and regeneration in zebrafish. Nat Commun. 2016;7:13787.
Leisegang MS, Fork C, Josipovic I, Richter FM, Preussner J, Hu J, et al. Long noncoding RNA MANTIS facilitates endothelial angiogenic function. Circulation. 2017;136:65–79.
Mehta G, Kumarasamy S, Wu J, Walsh A, Liu L, Williams K, et al. MITF interacts with the SWI/SNF subunit, BRG1, to promote GATA4 expression in cardiac hypertrophy. J Mol Cell Cardiol. 2015;88:101–10.
Li N, Kong M, Zeng S, Hao C, Li M, Li L, et al. Brahma related gene 1 (Brg1) contributes to liver regeneration by epigenetically activating the Wnt/β-catenin pathway in mice. FASEB J. 2019;33:327–38.
Li Z, Chen B, Dong W, Kong M, Shao Y, Fan Z, et al. The chromatin remodeler Brg1 integrates ROS production and endothelial-mesenchymal transition to promote liver fibrosis in mice. Front Cell Dev Biol. 2019;7:245.
Hang CT, Yang J, Han P, Cheng HL, Shang C, Ashley E, et al. Chromatin regulation by Brg1 underlies heart muscle development and disease. Nature. 2010;466:62–7.
Lin H, Zhu Y, Zheng C, Hu D, Ma S, Chen L, et al. Antihypertrophic memory after regression of exercise-induced physiological myocardial hypertrophy is mediated by the long noncoding RNA Mhrt779. Circulation. 2021;143:2277–92.
Lei H, Hu J, Sun K, Xu D. The role and molecular mechanism of epigenetics in cardiac hypertrophy. Heart Fail Rev. 2021;26:1505–14.
Bergmann MW. WNT signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac development. Circ Res. 2010;107:1198–208.
Malekar P, Hagenmueller M, Anyanwu A, Buss S, Streit MR, Weiss CS, et al. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension. 2010;55:939–45.
Cingolani OH. Cardiac hypertrophy and the Wnt/Frizzled pathway. Hypertension. 2007;49:427–8.
Oerlemans MI, Goumans MJ, van Middelaar B, Clevers H, Doevendans PA, Sluijter JP. Active Wnt signaling in response to cardiac injury. Basic Res Cardiol. 2010;105:631–41.
Wang N, Huo R, Cai B, Lu Y, Ye B, Li X, et al. Activation of Wnt/β-catenin signaling by hydrogen peroxide transcriptionally inhibits NaV1.5 expression. Free Radic Biol Med. 2016;96:34–44.
Gong W, Luo C, Peng F, Xiao J, Zeng Y, Yin B, et al. Brahma-related gene-1 promotes tubular senescence and renal fibrosis through Wnt/β-catenin/autophagy axis. Clin Sci. 2021;135:1873–95.
Gowda P, Patrick S, Singh A, Sheikh T, Sen E. Mutant isocitrate dehydrogenase 1 disrupts PKM2-β-catenin-BRG1 transcriptional network-driven CD47 expression. Mol Cell Biol. 2018;38:e00001-18.
Li J, Xu C, Liu Y, Li Y, Du S, Zhang R, et al. Fibroblast growth factor 21 inhibited ischemic arrhythmias via targeting miR-143/EGR1 axis. Basic Res Cardiol. 2020;115:9.
Lyu J, Wang M, Kang X, Xu H, Cao Z, Yu T, et al. Macrophage-mediated regulation of catecholamines in sympathetic neural remodeling after myocardial infarction. Basic Res Cardiol. 2020;115:56.
Liu Y, Li J, Xu N, Yu H, Gong L, Li Q, et al. Transcription factor Meis1 act as a new regulator of ischemic arrhythmias in mice. J Adv Res. 2022;39:275–89.
Cai B, Wang N, Mao W, You T, Lu Y, Li X, et al. Deletion of FoxO1 leads to shortening of QRS by increasing Na+ channel activity through enhanced expression of both cardiac NaV1.5 and β3 subunit. J Mol Cell Cardiol. 2014;74:297–306.
Stengl M, Ramakers C, Donker DW, Nabar A, Rybin AV, Spätjens RL, et al. Temporal patterns of electrical remodeling in canine ventricular hypertrophy: focus on IKs downregulation and blunted beta-adrenergic activation. Cardiovasc Res. 2006;72:90–100.
Wang Y, Liu J, Kong Q, Cheng H, Tu F, Yu P, et al. Cardiomyocyte-specific deficiency of HSPB1 worsens cardiac dysfunction by activating NFκB-mediated leucocyte recruitment after myocardial infarction. Cardiovasc Res. 2019;115:154–67.
Gerstenberger BS, Trzupek JD, Tallant C, Fedorov O, Filippakopoulos P, Brennan PE, et al. Identification of a chemical probe for family VIII bromodomains through optimization of a fragment hit. J Med Chem. 2016;59:4800–11.
Sharma T, Robinson DCL, Witwicka H, Dilworth FJ, Imbalzano AN. The Bromodomains of the mammalian SWI/SNF (mSWI/SNF) ATPases Brahma (BRM) and Brahma Related Gene 1 (BRG1) promote chromatin interaction and are critical for skeletal muscle differentiation. Nucleic Acids Res. 2021;49:8060–77.
Zhou Y, Chen Y, Zhang X, Xu Q, Wu Z, Cao X, et al. Brahma-related gene 1 inhibition prevents liver fibrosis and cholangiocarcinoma by attenuating progenitor expansion. Hepatology. 2021;74:797–815.
Trotter KW, Archer TK. The BRG1 transcriptional coregulator. Nucl Recept Signal. 2008;6:e004.
Barker N, Hurlstone A, Musisi H, Miles A, Bienz M, Clevers H. The chromatin remodelling factor Brg-1 interacts with beta-catenin to promote target gene activation. EMBO J. 2001;20:4935–43.
Chatterjee NA, Levy WC. Sudden cardiac death after myocardial infarction. Eur J Heart Fail. 2020;22:856–8.
Pouleur AC, Barkoudah E, Uno H, Skali H, Finn PV, Zelenkofske SL, et al. Pathogenesis of sudden unexpected death in a clinical trial of patients with myocardial infarction and left ventricular dysfunction, heart failure, or both. Circulation. 2010;122:597–602.
Yang J, Feng X, Zhou Q, Cheng W, Shang C, Han P, et al. Pathological Ace2-to-Ace enzyme switch in the stressed heart is transcriptionally controlled by the endothelial Brg1-FoxM1 complex. Proc Natl Acad Sci USA. 2016;113:E5628–35.
Vieira JM, Howard S, Villa Del Campo C, Bollini S, Dubé KN, Masters M, et al. BRG1-SWI/SNF-dependent regulation of the Wt1 transcriptional landscape mediates epicardial activity during heart development and disease. Nat Commun. 2017;8:16034.
Liu X, Yuan X, Liang G, Zhang S, Zhang G, Qin Y, et al. BRG1 protects the heart from acute myocardial infarction by reducing oxidative damage through the activation of the NRF2/HO1 signaling pathway. Free Radic Biol Med. 2020;160:820–36.
Zhang X, Liu S, Weng X, Zeng S, Yu L, Guo J, et al. Brg1 deficiency in vascular endothelial cells blocks neutrophil recruitment and ameliorates cardiac ischemia-reperfusion injury in mice. Int J Cardiol. 2018;269:250–8.
Li Z, Zhang X, Liu S, Zeng S, Yu L, Yang G, et al. BRG1 regulates NOX gene transcription in endothelial cells and contributes to cardiac ischemia-reperfusion injury. Biochim Biophys Acta Mol Basis Dis. 2018;1864:3477–86.
Rossow CF, Minami E, Chase EG, Murry CE, Santana LF. NFATc3-induced reductions in voltage-gated K+ currents after myocardial infarction. Circ Res. 2004;94:1340–50.
Peters NS, Coromilas J, Severs NJ, Wit AL. Disturbed connexin43 gap junction distribution correlates with the location of reentrant circuits in the epicardial border zone of healing canine infarcts that cause ventricular tachycardia. Circulation. 1997;95:988–96.
Dias P, Desplantez T, El-Harasis MA, Chowdhury RA, Ullrich ND, Cabestrero de Diego A, et al. Characterisation of connexin expression and electrophysiological properties in stable clones of the HL-1 myocyte cell line. PLoS One. 2014;9:e90266.
Zhang Y, Sun L, Xuan L, Pan Z, Hu X, Liu H, et al. Long non-coding RNA CCRR controls cardiac conduction via regulating intercellular coupling. Nat Commun. 2018;9:4176.
Lindsey ML, Escobar GP, Mukherjee R, Goshorn DK, Sheats NJ, Bruce JA, et al. Matrix metalloproteinase-7 affects connexin-43 levels, electrical conduction, and survival after myocardial infarction. Circulation. 2006;113:2919–28.
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).
Author information
Authors and Affiliations
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.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Ethical approval
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).
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41401-023-01170-y