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.

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 (_I_Na) and

transient outward potassium current (_I_to), 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. You have full access to this article via your institution. Download PDF SIMILAR CONTENT BEING VIEWED BY OTHERS

CARDIOMYOCYTE-SPECIFIC DELETION OF Β-CATENIN PROTECTS MOUSE HEARTS FROM VENTRICULAR ARRHYTHMIAS AFTER MYOCARDIAL INFARCTION Article Open access 06 September 2021 SPECIFIC DECREASING OF NA+

CHANNEL EXPRESSION ON THE LATERAL MEMBRANE OF CARDIOMYOCYTES CAUSES FATAL ARRHYTHMIAS IN BRUGADA SYNDROME Article Open access 17 November 2020 TEAD1 PROTECTS AGAINST NECROPTOSIS IN

POSTMITOTIC CARDIOMYOCYTES THROUGH REGULATION OF NUCLEAR DNA-ENCODED MITOCHONDRIAL GENES Article 19 January 2021 INTRODUCTION Ventricular arrhythmia (VA), a primary complication following

myocardial infarction (MI), is a major pathogenic factor for sudden cardiac death, posing a significant threat to patients’ lives [1]. The increased risk of VA in survivors of acute MI is

primarily due to ion channel remodeling and cardiac electrophysiological abnormalities caused by the infarction [2]. Nav1.5 carries out the depolarization that characterizes phase 0 of the

cardiac action potential (AP). Studies [3, 4] have shown that in a mouse model of MI, the expression of Nav1.5 is reduced, resulting in a decrease in the sodium current (_I_Na) density and a

slowing of the maximum depolarization rate in phase 0. These changes contribute to a decrease in the conduction velocity (CV) of the cardiac ventricle [3, 5]. Furthermore, studies [3, 6]

have demonstrated that the dysfunction or downregulation of Kv4.3/Kv4.2 leads to a decrease in the density of the transient outward potassium current (_I_to) in MI models, affecting the

phase 1 and the plateau level. Additionally, after MI, there is a decrease in the expression of Cav1.2, causing a significant reduction in the amplitude of the L-type calcium current

(_I_Ca-L) and the reappearance of the T-type calcium current [7]. Apart from ion channel changes, the downregulation of connexin43 (Cx43) in MI contributes to a reduction of cell connections

in the border zone of the infarcted heart. The disordered distribution and dysfunction of gap junctions in myocardial cells cause slow and uneven conduction, thereby exacerbating the

occurrence of arrhythmia in MI [8, 9]. Chromatin-recombinant Brahma-related gene-1 (BRG1), encoded by _SMARCA4_, is a crucial component of the Switch/Sucrose Non-Fermentable Chromatin

(SWI/SNF) complex. BRG1 plays a key role in regulating gene transcription by rearranging nucleosome positions and interacting with histone-bound DNA [10]. As a molecular chaperone, BRG1 [11]

interacts with various transcription factors or proteins such as microphthalmia-associated transcription factor (MITF) [12], β-catenin [13] and Smad3 [14], and is recruited to the promoter

region of the target gene to regulate transcription. The expression of BRG1 in cardiomyocytes is dynamic, it is highly expressed during embryonic development and is involved in the

proliferation and differentiation of myocardial cells. In adulthood, the expression of BRG1 decreases, but under pathological stimulation, it increases [15]. A previous study [12] has shown

that the upregulation of BRG1 during myocardial hypertrophy triggers the expression of GATA4, which ultimately results in the development of myocardial hypertrophy. Furthermore, BRG1

contributes to the development of myocardial hypertrophy by promoting the upregulation of myocardial β-myosin heavy chain (β-MHC) expression and the downregulation of α-myosin heavy chain

(α-MHC) expression [15]. Several studies [12, 16, 17] have indicated that BRG1 plays a crucial role in various cardiac physiological processes through the regulation of gene transcription.

However, whether BRG1 participates in arrhythmia after MI has not been reported. The Wnt/β-catenin pathway serves a pivotal function in cardiac hypertrophy, heart failure, and MI

[18,19,20,21]. Our preliminary study [22] demonstrated that in vitro, hydrogen peroxide inhibited Nav1.5 expression by activating the Wnt/β-catenin signaling pathway, and β-catenin

interacted with T-cell factor 4 (TCF4) to inhibit the transcription of _SCN5A_ by suppressing the activity of its promoter. In many pathological processes, β-catenin can recruit BRG1 to bind

to its target genes [13, 23, 24]. However, it is unknown whether the BRG1 and Wnt signaling pathways in vivo are involved in ion channel remodeling and arrhythmia after MI. Therefore, we

aimed to investigate the potential role of BRG1 in ion channel remodeling and VA after ischemic infarction. In the present study, we focused on elucidating the effect of BRG1 on cardiac

electrophysiological remodeling in MI. We sought to establish BRG1 as a disease-relevant factor that regulates the transcription of ion channels. MATERIALS AND METHODS ADENO-ASSOCIATED VIRUS

SEROTYPE 9 (AAV9) AND MOUSE MODEL OF MI Adult male C57BL/6 mice (20–25 g) were purchased from the Experimental Animal Center of Harbin Medical University (Grade II). Standard chow and water

were freely provided to the mice. The mice were housed under standard light-dark cycle (12 h/12 h), with a humidity range of 30%–70% and a constant temperature (23 ± 3 °C). The mice had _ad

libitum_ access to standard feed and water. The mice were anaesthetized with avertin, and then the left anterior descending artery (LAD) was ligated with 7–0 silk sutures to establish MI

models, and the electrocardiogram (ECG) changes in the mice were recorded. Occlusion was confirmed by the immediate whitening of the area perfused by the LAD; subsequently, the mice were

kept warm on a heating pad until recovery. Mice were injected with 7.5 × 1010 vg AAV9-BRG1-shRNA or AAV9-NC-shRNA through the tail vein. Sham mice underwent analogous surgery without

ligation of the coronary arteries. CULTURE OF NEONATAL MOUSE VENTRICULAR CARDIOMYOCYTES (NMVCS) AND TREATMENTS Neonatal mice (within 3 days after birth) were purchased from the Experimental

Animal Center of Harbin Medical University (Grade II). The NMVCs were isolated from the hearts of 1 to 3-day-old mice under SPF-grade conditions. The isolated hearts were then subjected to

multiple rounds of digestion using type II collagenase (Invitrogen, Carlsbad, USA), and the supernatants were collected. All cell suspensions were centrifuged at 1500 r/min for 7 min, and

the resulting precipitate was collected. The cells were then resuspended in the culture medium for 90 min, during which most cardiomyocytes (CMs) remained suspended. The suspended cells were

collected and cultured on a culture plate at a specific density. The cultured NMVCs were infected with plasmids (Genechem Co., Shanghai, China) to overexpress BRG1, BRG1-siRNA, TCF4-siRNA

and Scrambled-siRNA (GenePharma, Suzhou, China) using Lipofectamine 2000TM transfection reagent (Invitrogen, Carlsbad, CA, USA). To induce hypoxia, the cells were transferred to an anoxia

chamber (1% O2, 5% CO2) for 24 h. To inhibit BRG1, the cells were treated with 10 μM PFI-3 (Sigma-Aldrich, Saint Louis, USA), a BRG1 inhibitor, for 24 h. WESTERN BLOTTING ANALYSIS Total

protein samples were extracted from heart tissue or NMVCs for immunoblotting analysis. Equal amounts of protein (80 µg per well) was evenly loaded onto 7.5%–10% SDS polyacrylamide gels

(SDS‒PAGE), separated using the gels, and transferred to nitrocellulose (NC) membranes. The membranes were precut and blocked with rapid blocking solution (GenScript, USA) for 15 min at room

temperature. The membranes were then incubated overnight at 4 °C with primary antibodies, including rabbit GAPDH polyclonal antibody (Proteintech, 10494-1-AP, 1:1000), mouse anti-β-actin

(ZSGB-BIO, TA-09, 1:1000), rabbit BRG1 polyclonal antibody (Sigma-Aldrich, 07-478, 1:500), rabbit anti-Nav1.5 polyclonal antibody (Alomone labs, ASC-005, 1:500), rabbit anti-Kv4.3 polyclonal

antibody (Alomone labs, APC-017, 1:300), rabbit anti-Kv4.2 polyclonal antibody (Alomone labs, APC-023, 1:300), rabbit anti-TCF4 polyclonal antibody (Proteintech, 13838-1-AP, 1:1000), mouse

anti-β-Catenin (BD Transduction Laboratories, AB_397555, 1:2000), and rabbit anti-Cx43 antibody (PhosphoSitePlus, 3512S, 1:1000). The membranes were washed with PBST (phosphate-buffered

saline with Tween-20) three times and incubated with secondary antibodies for 1 h at room temperature. The membranes were then scanned and analyzed by an ODYSSEY machine (LI-COR, USA).

REAL-TIME QUANTITATIVE PCR Total RNA extractions from C57BL/6 mouse ventricular tissues and cultured NMVCs were performed using TRIzolTM Reagent (Invitrogen, USA). The RNA samples were then

reverse transcribed according to the manufacturer’s instructions (TOYOBO, ReverTra Ace® qPCR RT Kit, Shanghai, China). Real-time quantitative PCR (qRT-PCR) was performed using SYBR Green

Master on the ABI 7500 Fast Real-Time PCR system (Applied Biosystems, USA). The relative expression levels were calculated using the 2−ΔΔCT method. The primer sequences are listed in

Supplementary Table 1. CO-IMMUNOPRECIPITATION A total of 250 μg of nuclear protein per sample was extracted using a Nuclear Protein Extraction Kit (Beyotime, Shanghai, China) and incubated

overnight with 1 μg of primary antibody. Afterwards, magnetic beads in a 30 ml liquid suspension (MedChemExpress, USA) were added to the mixture and stirred overnight. The magnetic beads

were washed three times with cold PBST buffer on a magnetic stand. Finally, the supernatant was collected for Western blotting analysis. ELECTROCARDIOGRAPHY A bipolar limb lead biometric

signal acquisition and analysis system (BL-420S, Chengdu Taimeng, China) was used to record the surface standard lead II electrocardiogram (ECG) of mice in each group. QT intervals were

recorded using a BL-420S system with a range of 0.05–500 Hz. The corrected QT interval (QTc) was calculated as follows: QTc = QT/(RR/100)1/2. INTRA-CARDIAC ELECTROPHYSIOLOGY STUDIES After

each mouse was anaesthetized with avertin, a 1.1 F octapolar electrophysiology catheter (FTS-1113A-0518; Scisense, California, USA) was positioned in the right ventricle via the jugular

vein. The right ventricular pacing protocol included a ten-stimulus drive train (S1) at three cycle lengths (90, 80 and 70 ms), followed by S2 and S3 extrastimuli with 2 ms decrements. The

occurrence of rapid irregular ventricular rhythms lasting for three beats or more was considered to indicate a successful induction of VAs. EPICARDIAL OPTICAL VOLTAGE MAPPING The mice were

heparinized (heparin sodium injection, 400 IU ·kg−1). The hearts were isolated and then perfused in Langendorff mode with Tyrode’s solution (in mM: 127 NaCl, 1.72 CaCl2, 4.7 KCl, 1.54

NaH2PO4, 1.0 MgCl2•6H2O, 11.1 glucose and 20 NaHCO3, pH 7.35 with NaOH) at 37 °C. The solution was gassed with a mixture of 95% O2 and 5% CO2 for 15 min. After 10 min of stabilization, the

hearts were perfused with (±)-blebbistatin (10 μmol/L, Selleckchem, Houston, TX, USA) to uncouple contraction from excitation. After perfusion, the hearts were stained with the

voltage-sensitive dye RH237 (Invitrogen, Carlsbad, CA). The fluorescence was filtered and simultaneously recorded with a CMOS camera (MiCAM05 Ultima, SciMedia, California, USA). The

fluorescence was recorded at a frame rate of 1 frame/ms in an image of 100 × 100 pixels with a pixel size of 100 μm × 100 μm per pixel. Customized software (SciMedia, Costa Mesa, CA) was

used to calculate the CV. SINGLE VENTRICULAR CARDIOMYOCYTE ISOLATION Under anesthesia, the mice were euthanized by cervical dislocation. The hearts were quickly isolated, cannulated, and

perfused with nominally Ca2+-free oxygenated Tyrode’s solution (in mM:150 NaCl, 5.4 KCl, 2 NaH2PO4, 1.2 MgCl2•6H2O, 5 HEPES, and 10 glucose; pH 7.35) for 5 min. Subsequently, the hearts were

perfused with the same solution combined with 1 mg/ml type II collagenase (Invitrogen, Carlsbad, USA) to digest tissue. Once the hearts became soft, the ventricular tissues were isolated,

cut into small pieces, and dispersed. The cells were then transferred into Tyrode’s solution containing 0.2 mM CaCl2 and 1% bovine serum albumin for preservation. PATCH-CLAMP EXPERIMENTS All

whole-cell patch-clamp experiments were recorded with whole-cell patch-clamp equipment (an Axopatch 700B amplifier). Microelectrodes were pulled from borosilicate glass electrodes using a

Brown-Flamming puller (model P-97, Sutter Instrument Co., Novato, CA., UAS) and had pipette resistances of 1.8 to 2.5 MΩ. For the measurement of _I_Na in NMVCs, the pipette filling solution

contained the following (in mM): 5 NaCl, 35 _L_-aspartic acid, 30 TEACl, 11 HEPES, 5 Mg-ATP, 10 EGTA, and 125 CsOH, and the pH of the solution was adjusted to 7.35 with CsOH. The

extracellular solution contained the following (in mM): 10 NaCl, 1.2 MgCl2•6H2O, 125 TEACl, 1.8 CaCl2, 20 HEPES, 5 CsCl, 10 glucose, and 3 4-AP, pH 7.3. For the measurement of _I_Na in

isolated mouse ventricular cardiomyocytes, the pipette solution contained the following (in mM): 10 NaF, 110 CsF, 20 CsCl, 10 EGTA, and 10 HEPES (pH adjusted to 7.35 with CsOH). The

extracellular solution contained the following (in mM): 145 NaCl, 4.5 CsCl, 1.5 MgCl2, 1 CaCl2, 5 HEPES, 5 glucose, and 0.1 CdCl2, (pH 7.35). Voltage-dependent activation and steady-state

inactivation profiles of _I_Na were assessed by fitting the data with the Boltzmann equation. For the measurement of _I_to in NMVCs and isolated ventricular cardiomyocytes, we used an

extracellular solution containing the following (in mM): 126 NaCl, 5.4 KCl, 0.33 NaH2PO4, 1.0 MgCl2•6H2O, 2.38 CaCl2, 10 HEPES, and 11.11 glucose (pH 7.35). The pipette filling solution

contained (in mM) 20 KCl, 110 KOH, 110 aspartic acid, 10 HEPES, 1 MgCl2, 10 EGTA and 5 ATP-Na2 (pH adjusted to 7.3 with NaOH). Each current amplitude data point was normalized to battery

capacitance (current density, pA/pF) data. The current-voltage relationships (_I_-_V_ curve) were plotted. The APs were recorded with a pipette filling solution containing (in mM) 20 KCl,

110 KOH, 110 aspartic acid, 10 HEPES, 1 MgCl2, 10 EGTA and 5 ATP-Na2 (pH adjusted to 7.3 with NaOH). The extracellular solution contained (in mM) 126 NaCl, 5.4 KCl, 0.33 NaH2PO4, 1.0

MgCl2•6H2O, 2.38 CaCl2, 10 HEPES, and 11.11 glucose (pH 7.35). IMMUNOFLUORESCENCE STAINING Cardiomyocytes freshly isolated from ventricular myocardium were fixed in 4% paraformaldehyde for

15–30 min, permeabilized with 0.4% Triton X-100 (Biotopped, Beijing, China) at room temperature for 30–60 min and co-incubated with primary antibodies, including mouse anti-α-Actinin

(ab50599, Abcam, Cambridge, UK, 1:100), rabbit BRG1 polyclonal antibody (Sigma-Aldrich, 07-478, 1:500), rabbit anti-Nav1.5 polyclonal antibody (Alomone labs, ASC-005, 1:500), rabbit

anti-Kv4.3 polyclonal antibody (Alomone labs, APC-017, 1:300). Afterwards, the cardiomyocytes were incubated with the appropriate secondary antibodies at room temperature for 2 h. The nuclei

were then stained with DAPI (Beyotime, Shanghai, China). Fluorescence was visualized with an inverted ZEISS fluorescence confocal microscope. All images were processed in an identical

manner to faithfully capture the real-time appearance of each sample. Treble-Fluorescence immunohistochemical mouse/rabbit kit (immunoway, LA, USA) was used for four-color fluorescence

co-localization. HISTOLOGICAL STAINING For histological studies, after the blood was removed by retrograde perfusion from the apex with cold PBS, cardiac samples were fixed with 4%

paraformaldehyde, embedded in paraffin, and sectioned in the transverse plane to a thickness of 5 μm. The sections were stained with hematoxylin and eosin (H&E) as well as Masson’s

trichrome (Solarbio, Beijing, China). The area of cardiac fibrosis and MI was visualized under a microscope (Zeiss, Germany). TRIPHENYL TETRAZOLIUM CHLORIDE (TTC) STAINING For TTC staining,

the hearts were fixed in 4% PFA for 24 h, embedded in paraffin, and cut into 2 μm-thick slices. The slices were washed with 0.9% saline and then stained with 2.0% TTC (Solarbio, Beijing,

China) in the dark at 37 °C for 20 min. A stereomicroscope (Zeiss, Jena, Germany) was used to take images of the slices. The infarct area (pale area) and the non-infarct area (red area) were

calculated by ImageJ software. ECHOCARDIOGRAPHY Adult male C57BL/6 mice were anesthetized with 2% avertin (0.1 ml/10 g body weight, Sigma-Aldrich Corporation, MO, USA). Left ventricular

function was assessed by the VINNO 6 imaging system (VINNO, Suzhou, Chinese) for M-mode echocardiography. TRANSMISSION ELECTRON MICROSCOPY Heart samples were fixed in 2.5% glutaraldehyde/1%

osmium tetroxide and embedded in epoxy resin. Small tissue blocks were counterstained with uranyl acetate and lead citrate. The samples were then tested, and images were obtained using a

JEM-1200 electron microscope (JEOL Ltd., Japan). LUCIFERASE PROMOTER ASSAYS Lipofectamine 2000, and Opti-MEM reagents (Invitrogen, Carlsbad, CA, USA) were used to transfect _SNC5A_ and

_KCND3_ reporters, _Smarca4_ plasmids and BRG1-siRNA (Genechem, Shanghai, China) into HEK-293 cells. Forty-eight hours after transfection, the cells were harvested and lysed for luciferase

assays. The luminescence intensity of the luciferase catalytic substrate after transfection was determined using a GLOMAX 20/20 fluorescence luminescence detector. CHROMATIN

IMMUNOPRECIPITATION (CHIP) ASSAYS ChIP assays were performed using ChIP assay kit materials (Thermo Scientific, MA, USA). NMVCs were subjected to ChIP assays using anti-BRG1 (Proteintech,

IL, USA), TCF4 (Proteintech, IL, USA) antibodies, or rabbit IgG (Cell Signaling Technology, Danvers, MA, USA). DNA was immunoprecipitated from the sonicated cell lysates using BRG1, TCF4, or

IgG antibodies, and PCR was performed to amplify the binding sites. For Re-ChIP, the protein-DNA-head complex was washed three times with ChIP washing buffer, and then washed twice with 1×

TE buffer. The immunoprecipitated protein-DNA complex was then eluted by incubation at 37 °C for 30 min in 75 μl of Re-ChIP elution buffer. After centrifugation, the supernatant was

separated, and the sample was diluted 20 times with ChIP dilution buffer containing 50 μg of bovine serum albumin and a protease inhibitor. The second immunoprecipitation reaction was

performed with anti-β-Catenin (BD Transduction Laboratories), BRG1 and rabbit IgG. STATISTICAL ANALYSIS All data were presented as mean ± standard deviation (SD). Data were analyzed using

GraphPad Prism (v8.0; GraphPad Software, USA) software. A two-tailed Student’s unpaired _t_ test was used to analyze the differences between two variables. Differences among groups were

evaluated using one-way ANOVA followed by Tukey’s test or Dunnett’s test for _post hoc_ comparison when appropriate. _P_ values < 0.05 were considered statistically significant. RESULTS

DYNAMIC EXPRESSION OF BRG1 AFTER MI MI models were established in mice by ligating the left anterior descending coronary artery at various time points. Western blotting analysis showed a

progressive increase in BRG1 levels in the border zone following MI; the values reached a peak on the 7th day and remained elevated thereafter (Fig. 1a). Immunofluorescence staining further

confirmed the localization and enhanced expression of BRG1 in cardiomyocytes 7 days after MI (Fig. 1b). Based on these results, we chose the 7th day after MI as the time point for the

following experiments. BRG1 KNOCKDOWN REDUCED THE SUSCEPTIBILITY TO VA AND CARDIAC DYSFUNCTION AFTER MI VA is a primary complication following MI [25, 26]. Therefore, we sought to determine

whether the downregulation of BRG1 is involved in cardiac electrophysiological remodeling and VA after MI. AAV9-BRG1-shRNA and AAV9-NC-shRNA were delivered into mice via tail vein injection,

and 3 weeks after injection, an MI model was established in mice (Fig. 2a). Three weeks after injection, we examined the expression of BRG1 in mouse cardiomyocytes and found that

AAV9-BRG1-shRNA injection significantly decreased its expression, while other tissues, such as the lung, kidney, and liver were not affected (Fig. S1). On the 7th day after MI, we observed

that the susceptibility to electrical-induced ventricular fibrillation (VF) and the duration of arrhythmia were markedly reduced by the knockdown of BRG1 (Fig. 2b–d). Additionally,

electrocardiograms (ECGs) showed that the QTc intervals were lengthened slightly in MI mice. However, the QTc intervals were shortened after BRG1 knockdown in MI mice. (Fig. 2e, f).

Furthermore, we also found that knockdown of BRG1 protected against cardiac dysfunction, as illustrated by the increases in the ejection fraction (EF) and fractional shortening (FS), as

shown in the left ventricle (LV) advancement (decreases in LV internal diameter at diastolic phase, LV internal diameter at systolic phase, LV end-diastolic volume, and LV end-systolic

volume) in Fig. S2. Moreover, the infarct size and interstitial fibrosis area were markedly reduced in MI mouse hearts treated with AAV9-BRG1-shRNA compared to those treated with

AAV9-NC-shRNA (Fig. S3). These data suggested that downregulation of BRG1 decreased the susceptibility to VAs and cardiac dysfunction after MI in mice. BRG1 KNOCKDOWN AMELIORATED ADVERSE

ELECTRICAL REMODELING AFTER MI Increases in QTc intervals were found in MI mice (Fig. 2f), compatible with abnormalities in ventricular repolarization and conduction [27]. To characterize

the epicardial conduction of MI mouse hearts treated with AAV9-BRG1-shRNA, we performed optical voltage mapping of Langendorff-perfused hearts. A representative color activation map obtained

by electrode pacing at a cycle length of 200 ms in each group was presented in Fig. 3a. The ventricular electrical CV in MI mice was significantly slower than that in the Sham group, as

shown in Fig. 3b, and this abnormal electrical conduction was ameliorated in AAV9-BRG1-shRNA-infected MI mice. A sample color repolarogram obtained from a ventricular-paced heart and the

traces of optical action potentials obtained from ventricular-paced hearts with a 200 ms cycle length were shown in Fig. 3c, d. Ventricular action potential durations (APDs) at 30%, 50% and

90% repolarization were lengthened in MI hearts and were shortened by knockdown of BRG1 (Fig. 3e–g). Furthermore, whole-cell patch-clamp techniques were used to record the APs of single

ventricular myocyte acutely isolated from mouse hearts. In agreement with the modest QTc prolongation observed in MI mice, APD, APD50 and APD30 in MI mice and AAV9-NC-shRNA-treated MI mice

presented a similar prolongation in Fig. 4a–d, which were significantly shortened by BRG1 knockout in MI mice. These results revealed that the downregulation of BRG1 ameliorated abnormal 

conduction slowing and repolarization delay. Previous studies [28, 29] have confirmed that the changes observed as a consequence of ventricular electrophysiological dysfunction in post-MI

patients and animal models involve the remodeling of ion channels such as sodium and potassium channels. Interestingly, we found that BRG1 knockdown regulated the mRNA levels of Nav1.5 and

Kv4.3, while Kir2.1, Kv4.2, Kv1.5 and Cav1.2 showed no alterations in BRG1 knockdown mice (Fig. S4). We used whole-cell patch-clamp techniques to record the _I_Na and _I_to of single

ventricular myocyte acutely isolated from mouse heart. The current densities of _I_Na (Fig. 4f) and _I_to (Fig. 4k) of cardiomyocytes from MI mice and AAV9-NC-shRNA-treated MI mice were

markedly reduced. Strikingly, the reductions were reversed by knockdown of BRG1. To further confirm the effects of BRG1 knockdown on Na+ channel activation, inactivation and reactivation in

MI mice, the steady-state activation, steady-state inactivation and recovery from inactivation of _I_Na were recorded and analyzed. There was no significant difference in the inactivation or

reactivation of Na+ channels among the groups (Fig. 4h, i). Steady-state activation of the Na+ channel showed an apparent right shift in the MI and MI + AAV9-NC-shRNA group compared with

the Sham group, which suggested that the activation of Nav1.5 was slowed down, and the right shift was relieved by knockdown of BRG1 in MI mice, which had no statistical differences (Fig. 

4g). These results indicated the amelioration of cardiac conduction and repolarization delay is presumably due to downregulation of BRG1, which improved the decreased densities of _I_Na and

_I_to. In addition to the electrophysiological changes above, gap junctions ruptured in the border zone of infarcted hearts in the MI group and AAV9-NC-shRNA-treated MI group as observed by

scanning electron microscopy, and BRG1 knockdown mitigated the adverse alterations in gap junctions in MI mice (Fig. S5a). We then investigated the protein levels of Cx43, which were

markedly decreased in the MI group but significantly increased in the AAV9-BRG1-shRNA treatment group (Fig. S5b). BRG1 KNOCKDOWN RESCUED THE DEFICIENCY OF NAV1.5 AND KV4.3 CHANNELS AFTER MI

The above data showed that BRG1 knockdown rescued VA in MI mice by restoring _I_Na and _I_to. We further explored the influences of BRG1 knockdown on the expression of BRG1/_SMARCA4_,

Nav1.5/_SCN5A_ and Kv4.3/_KCND3_ in the border zone of infarcted hearts. The expression of BRG1 increased after MI, which was reversed by AAV9-BRG1-shRNA treatment (Fig. 5a, b). On the other

hand, knockdown of BRG1 prevented the reduced expression of Nav1.5 and Kv4.3 after MI (Fig. 5a–c). Concordantly, when we measured the protein levels of Nav1.5 and Kv4.3 by

immunofluorescence staining, we demonstrated that BRG1 knockdown attenuated the downregulation of Nav1.5 and Kv4.3 protein in MI mouse hearts (Fig. 5d–g). These results indicated that BRG1

knockdown after MI improved the reduction in the protein and mRNA levels of Nav1.5 and Kv4.3, consistent with the induction of increased densities of _I_Na and _I_to. INHIBITION OF BRG1

INFLUENCED THE CHANGES IN NAV1.5/_I_ NA AND KV4.3/_I_ TO INDUCED BY HYPOXIA In vitro, hypoxia was used to mimic ischemia in NMVCs [30]. We silenced BRG1 in NMVCs with a specific small

interfering RNA (siRNA). Consistent with the data observed in acutely isolated cardiomyocytes from mouse hearts, in hypoxia-induced NMVCs protein levels of BRG1 markedly increased, which

were reversed by BRG1-siRNA treatment, while the levels of Nav1.5 and Kv4.3 were significantly reduced in the hypoxia group and hypoxia + Scrambled-siRNA group, which were also reversed by

BRG1-siRNA treatment (Fig. 6a–c). Then, we observed the effects of BRG1 on _I_Na and _I_to by whole-cell patch-clamp, which showed that after NMVCs were exposed to hypoxic conditions, the

current density and peak of _I_Na were greatly reduced compared with those of the control group, and _I_Na density significantly decreased at the voltages from −45 to −5 mV (Fig. 6d). Next,

the effectiveness of BRG1-siRNA treatment in downregulating _I_to in hypoxia-induced NMVCs was demonstrated (Fig. 6e). These data indicated that BRG1 knockdown in vitro improved Nav1.5 and

Kv4.3 channel remodeling in hypoxia-induced NMVCs. To determine whether BRG1 inhibition has therapeutic potential for the effects of hypoxia on Nav1.5 and Kv4.3 channels, we treated

hypoxia-exposed NMVCs with PFI-3 [31, 32], a specific inhibitor targeting BRG1 [33], to treat the hypoxia-induced NMVCs. In hypoxia-induced NMVCs, the protein and mRNA levels of Nav1.5 and

Kv4.3 were markedly reduced, which was significantly reversed by the addition of PFI-3 but not DMSO (Fig. 6f–h). OVEREXPRESSION OF BRG1 WORSENED NAV1.5/_I_ NA AND KV4.3/_I_ TO We further

hypothesized that overexpression of BRG1 regulated Nav1.5 and Kv4.3 channels and influenced _I_Na and _I_to. We used a plasmid to overexpress BRG1 in NMVCs (Fig. S6a), and BRG1

overexpression induced a reduction in Nav1.5 and Kv4.3 (Fig. S6a–e). The _I_Na density significantly decreased at voltages from −45 to 0 mV, while the density of _I_to decreased at voltages

from −20 to 60 mV (Fig. S6f, g). Therefore, BRG1 exhibited negative regulation of Nav1.5 and Kv4.3 and further influenced _I_Na and _I_to. BRG1 AND Β-CATENIN BOUND TO TCF4 IN THE NUCLEUS

AFTER MI AND HYPOXIA BRG1 is a major coregulator of transcription, interacting with transcription factors or histone-binding factors to target gene promoters, which results in the inhibition

of gene expression [34]. Numerous studies [13, 24, 33, 35] reported that BRG1 specifically bound to β-catenin to regulate the transcription of its target gene. Our recent research [22]

found that H2O2, an oxidant, could activate the Wnt/β-catenin signaling and promote the nuclear translocation of β-catenin, and the nuclear trafficking β-catenin interacted with TCF4 to

transcriptionally inhibit cardiac Nav1.5 expression. Surprisingly, we found that the expression of β-catenin and BRG1 in the nucleus was enhanced after MI and hypoxia (Fig. 7a). Furthermore,

immunofluorescence staining and co-immunoprecipitation confirmed that binding was enhanced among TCF4, BRG1 and β-catenin in MI hearts (Fig. 7a, b) and in hypoxia-induced NMVCs (Fig. S7).

Together, these results suggested that after MI and hypoxia β-catenin translocated into the nuclei and bound to BRG1 and TCF4 (Figs. 7 and S7). BRG1/Β-CATENIN/TCF4 MEDIATED THE

TRANSCRIPTIONAL SUPPRESSION OF NAV1.5 AND KV4.3 CHANNELS According to the jasper website, we predicted the potential binding sites of TCF4 in the region of the _SCN5A_ and _KCND3_ promoters

(Fig. 8a, b) and then transfected reporter genes containing the _SCN5A_ and _KCND3_ promoters into HEK293 cells to detect the regulatory effect of BRG1 on the _SCN5A_ and _KCND3_ promoters

by luciferase reporter assays. Compared with the control conditions, knockdown of BRG1 and treatment with PFI-3 significantly promoted the activity of the _SCN5A_ and _KCND3_ promoters,

while overexpression of BRG1 reduced the activity of both promoters. PFI-3 could also rescue the decreased promoter activity of _SCN5A_ and _KCND3_ caused by BRG1 overexpression (Fig. 8a–e),

suggesting that BRG1 has a regulatory effect on the _SCN5A_ and _KCND3_ promoters. This analysis revealed that BRG1-based _SCN5A_/_KCND3_ regulation was controlled by potential binding

sites located on the _SCN5A_ promoter region between −2000 and 0 bp, and on the _KCND3_ promoter region between −2000 and −181 bp (Fig. 8a, b). ChIP assays further showed that TCF4 and BRG1

clustered on the _SCN5A_ promoter region (−1483 bp to −1240 bp) (Fig. 8f) and _KCND3_ promoter region (−460 bp to −227 bp) (Fig. 8i). Excitingly, this region was also found to recruit BRG1

and β-catenin (Fig. 8h, k). These results suggested that TCF4, as a transcription factor, bound to the promoter regions of _SCN5A_ and _KCND3_ and recruited BRG1 and β-catenin as molecular

chaperones to form complexes that inhibited _SCN5A_ and _KCND3_ transcription. Furthermore, Western blotting and qRT-PCR results showed the changes in the protein and mRNA levels of Nav1.5

and Kv4.3 induced by hypoxia were ameliorated after TCF4 knockdown (Fig. S8b). The same result could be found by simulating anoxic injury with BRG1 overexpression (Fig. S8c). These results

indicated that after MI the increased BRG1 and β-catenin bound to TCF4, forming a BRG1/β-catenin/TCF4 transcription complex and regulating the transcription of _SCN5A_ and _KCND3_ (Fig. 9).

DISCUSSION Survivors of MI may face an increased risk developing of malignant VAs, including ventricular tachycardia, VF, and other life-threatening arrhythmias. These arrhythmias are the

leading cause of sudden cardiac death following MI, and electrophysiological remodeling is the main culprit behind the occurrence of malignant arrhythmias [36]. The electrophysiological

remodeling process following MI is characterized by alterations in the currents of multiple ion channels, as well as prolongation of the AP [37]. In this study, we report the novel

observation that a lack of BRG1 in the heart attenuated ischemia-induced dysfunction of Nav1.5 and Kv4.3, thereby reducing the incidence of VAs after MI in mice. BRG1 is the core component

of the chromatin remodeling complex SWI/SNF, and has emerged as a key regulator of cardiac diseases including myocardial hypertrophy [16, 38], MI [39, 40], and cardiac ischemia‒reperfusion

[41]. In hearts, BRG1 levels were dynamically changed in postnatal [15] and in response to pathologic stimuli [12], which has been demonstrated to aggravate cardiac hypertrophy [12] and

ischemia‒reperfusion injury [42]. Consistent with a previous study [40], our results showed a progressive increase in BRG1 in the border zone of the post-MI heart. Cardiac-specific deletion

of BRG1 could ameliorate cardiac electrophysiological remodeling after MI by mitigating the susceptibility to electrical-induced VAs, shortening the QTc interval and ameliorating anomalous

repolarization and conduction in MI hearts. A substantial body of evidence [3, 25, 27, 43] revealed that abnormalities in ventricular repolarization and conduction accompany reduced _I_to

and _I_Na, and decreased expression of Kv4.3 and Nav1.5. Nonetheless, the mechanism, particularly in the transcriptional mechanism, behind the dysfunction of these channels in MI remains

unclear. Intriguingly, BRG1 can bind to the promoter region of _SCN5A_/_KCND3_, and knockdown of BRG1 can rescue the reduction in Nav1.5 and Kv4.3 in cardiomyocytes and reverse the

shortening of CV and APD. Cardiac-specific deletion of BRG1 reversed the reduction in the densities of _I_to and _I_Na and had no impact on the steady-state activation, steady-state

inactivation or recovery from inactivation of _I_Na. Previous studies [9, 44, 45] have extensively reported that the slowing of conduction and the subsequent increased risk of arrhythmias

after MI are partly attributable to the downregulation of Cx43 and Nav1.5. This downregulation leads to a decrease in CV and creates a substrate for the development of arrhythmias. Zhang et

al. demonstrated that after MI, decreased Cx43 in the gap junction led to slow CV and scattered pulse propagation [46], and we found that knockdown of BRG1 mitigated the adverse alterations

of gap junctions and increased the expression of Cx43 in MI mice. In the context of MI, conduction abnormalities may arise due to the downregulation of specific ion channels and the

disruption of gap junctions involved in the generation and propagation of electrical impulses [45]. Consistent with a previous study [3], our results showed a reduced CV in MI hearts.

Moreover, slowing of the CV can disrupt the synchronized contraction of the heart chambers and increase the risk of arrhythmias [47]. However, BRG1 knockdown ameliorated the decelerated CV

by improving the abnormal expression of Nav1.5 and Cx43 after MI, thereby significantly reducing susceptibility to VA following MI. In vitro, we also found that the decrease in Nav1.5 and

Kv4.3 induced by hypoxia was rescued by BRG1 knockdown and PFI-3 treatment. Our results suggested that knockdown of BRG1 exerted a protective role in cardiac electrical remodeling and

arrhythmia after MI. In addition, BRG1 knockdown improved cardiac function, decreased infarct size, and suppressed cardiac fibrosis in MI mouse hearts. These protective effects of BRG1

knockdown on myocardial ischemia were confirmed in Figs. S2 and S3. The findings implied that the anti-arrhythmic effect of BRG1 knockdown could be attributed, in part, to its anti-ischemic

impact. As a co-transcription factor, β-catenin plays a crucial role in cardiac disease. Nuclear translocation of β-catenin has been extensively reported to be involved in cardiac

hypertrophy, heart failure, and MI [18, 19]. Importantly, a previous study has also reported [22] that H2O2 promotes nuclear translocation of β-catenin; when localized in the nucleus,

β-catenin interacts with TCF4 to bind to the _SCN5A_ promoter. We also confirmed that after MI, β-catenin translocated to the nucleus and bound to BRG1, which was enhanced after MI; and the

increased BRG1 and β-catenin in nucleus, were recruited to form a transcription complex with TCF4. Using a ChIP assay, we confirmed that TCF4 could bind to the promoter regions of _SCN5A_

and _KCND3_, and BRG1 and β-catenin were also detected in this region. Luciferase reporter assays indicated that BRG1 deficiency significantly promoted the activity of the _SCN5A_ and

_KCND3_ promoters, while overexpression of BRG1 reduced the activity of both promoters. It manifested that BRG1 was essential for the transcriptional repression of _SCN5A_ and _KCND3_. In

conclusion, we demonstrated the function of BRG1 in malignant VA in post-MI mice. For the first time, we observed that knockdown of BRG1 attenuated ischemia-induced dysfunction of Nav1.5 and

Kv4.3, thereby reducing the incidence of VAs after MI. Mechanistically, after MI, nuclear-translocated β-catenin and increased BRG1 bound to TCF4, forming a BRG1/β-catenin/TCF4

transcription complex to suppress the transcriptional activity of _SCN5A_ and _KCND3_. This study provides a piece of evidence that inhibition of BRG1 has anti-arrhythmic effects, and

highlights a new potential therapy targeting BRG1 for the treatment of ischemic arrhythmia. 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed

  Google Scholar  * 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. Article  PubMed  Google Scholar  * 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. Article  CAS  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS 

PubMed  PubMed Central  Google Scholar  * 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. Article  PubMed  Google Scholar  * 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. Article  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google

Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  PubMed  Google Scholar  * Bergmann MW. WNT signaling in adult cardiac hypertrophy and remodeling: lessons learned from cardiac

development. Circ Res. 2010;107:1198–208. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * Cingolani OH. Cardiac hypertrophy and the

Wnt/Frizzled pathway. Hypertension. 2007;49:427–8. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  *

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.

Article  CAS  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  PubMed

Central  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article

  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * Trotter KW, Archer TK. The BRG1

transcriptional coregulator. Nucl Recept Signal. 2008;6:e004. Article  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * Chatterjee NA, Levy

WC. Sudden cardiac death after myocardial infarction. Eur J Heart Fail. 2020;22:856–8. Article  PubMed  Google Scholar  * 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. Article  PubMed  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  * 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. Article  PubMed  PubMed Central  Google

Scholar  * 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. Article 

PubMed  PubMed Central  Google Scholar  * 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. Article  CAS  PubMed  Google Scholar  Download references 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 Author notes * These authors contributed equally: Jing Li, Zi-yue Ma AUTHORS AND AFFILIATIONS * 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 * Heilongjiang Academy of Medical

Sciences, Baojian Road, Nangang District, Harbin, 150081, China Tao Ban Authors * Jing Li View author publications You can also search for this author inPubMed Google Scholar * Zi-yue Ma

View author publications You can also search for this author inPubMed Google Scholar * Yun-feng Cui View author publications You can also search for this author inPubMed Google Scholar *

Ying-tao Cui View author publications You can also search for this author inPubMed Google Scholar * Xian-hui Dong View author publications You can also search for this author inPubMed Google

Scholar * Yong-zhen Wang View author publications You can also search for this author inPubMed Google Scholar * Yu-yang Fu View author publications You can also search for this author

inPubMed Google Scholar * Ya-dong Xue View author publications You can also search for this author inPubMed Google Scholar * Ting-ting Tong View author publications You can also search for

this author inPubMed Google Scholar * Ying-zi Ding View author publications You can also search for this author inPubMed Google Scholar * Ya-mei Zhu View author publications You can also

search for this author inPubMed Google Scholar * Hai-jun Huang View author publications You can also search for this author inPubMed Google Scholar * Ling Zhao View author publications You

can also search for this author inPubMed Google Scholar * Hong-zhao Lv View author publications You can also search for this author inPubMed Google Scholar * Ling-zhao Xiong View author

publications You can also search for this author inPubMed Google Scholar * Kai Zhang View author publications You can also search for this author inPubMed Google Scholar * Yu-xuan Han View

author publications You can also search for this author inPubMed Google Scholar * Tao Ban View author publications You can also search for this author inPubMed Google Scholar * Rong Huo View

author publications You can also search for this author inPubMed Google Scholar 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 Correspondence to Tao Ban or Rong Huo. 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). SUPPLEMENTARY INFORMATION FIGURE S1 FIGURE S2 FIGURE S3 FIGURE S4 FIGURE S5 FIGURE S6 FIGURE S7 FIGURE S8

SUPPLEMENTARY MATERIALS 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.

Reprints and permissions 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 Download citation * Received: 22 May 2023 * Accepted: 14 September 2023 * Published: 25

October 2023 * Issue Date: March 2024 * DOI: https://doi.org/10.1038/s41401-023-01170-y SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get

shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS *

myocardial infarction * ventricular arrhythmia * BRG1 * Nav 1.5 channel * Kv 4.3 channel * action potential duration