Direct and Indirect Suppression of Scn5a Gene Expression Mediates Cardiac Na+ Channel Inhibition by Wnt Signalling

Lu, Aizhu; Kamkar, Maryam; Chu, Cencen; Wang, Jerry; Gaudet, Kaya; Chen, Yawen; Lin, Lauren; Liu, Weixin; Marbán, Eduardo; Liang, Wenbin

doi:10.1016/j.cjca.2019.09.019

Cited by 17 publications

(25 citation statements)

References 46 publications

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“…( E) Protocols for evaluation of the inducibility of ventricular tachyarrhythmias (VT). Left Panel: Mouse hearts were isolated and Langendorff-perfused with Tyrode solution containing isoproterenol, ex vivo ECG were continuously measured by placing recording electrodes around the heart as we previously described 23 , 54 . Programmed electrical stimulation (PES) was applied using a MyoPacer (IonOptix) via a pair of platinum electrodes placed on the left ventricular apex of the heart.…”

Section: Resultsmentioning

confidence: 99%

“…To investigate the susceptibility of mice to ventricular arrhythmias, we used a protocol that we recently developed for rodent hearts 23 , 33 that combined adrenergic stimulation (with isoproterenol) and progressive programmed electrical stimulation (PES) in isolated, Langendorff-perfused hearts (Fig. 1 E), while ex vivo ECG was recorded by placing electrodes around the heart.…”

Section: Resultsmentioning

confidence: 99%

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Cardiomyocyte-specific deletion of β-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction

Wang

Xia

et al. 2021

Sci Rep

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Wnt/β-catenin signaling is activated in the heart after myocardial infarction (MI). This study aims to investigate if β-catenin deletion affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at 8 weeks after MI, associated with reduced scar size and attenuated chamber dilation. qPCR analyses of both myocardial tissues and purified cardiomyocytes demonstrated upregulation of Wnt pathway genes in border and infarct regions after MI, including Wnt ligands (such as Wnt4) and receptors (such as Fzd1 and Fzd2). At 1 week after MI, cardiac sodium channel gene (Scn5a) transcript was reduced in WT but not in KO hearts, consistent with previous studies showing Scn5a inhibition by Wnt/β-catenin signaling. At 8 weeks after MI when Wnt genes have declined, Scn5a returned to near sham levels and K+ channel gene downregulations were not different between WT and KO mice. This study demonstrated that VT susceptibility in the chronic phase after MI is reduced in mice with cardiomyocyte-specific β-catenin deletion primarily through attenuated structural remodeling, but not ion channel gene alterations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Cardiomyocyte-specific deletion of β-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction

Wang

Xia

et al. 2021

Sci Rep

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“…To investigate the susceptibility of mice to ventricular arrhythmias, we used a protocol that we recently developed for rodent hearts 20,30 that combined adrenergic stimulation (with isoproterenol) and progressive programmed electrical stimulation (PES) in isolated, Langendorff-perfused hearts (Figure 1E), while ex vivo ECG was recorded by placing electrodes around the heart. With this protocol, ventricular tachycardias (VT, de ned as three or more consecutive ectopic ventricular beats) were successfully induced in 77% (10/13) post-MI WT mice at week 8, but in none (0/18) of the sham-operated WT mice (Figure 1F and 1G) validating our VT-inducing protocol.…”

Section: Resultsmentioning

confidence: 99%

“…Programmed electrical stimulation (PES) in isolated mouse hearts At 1 and 8 weeks after MI, mouse hearts were isolated and Langendorff-perfused with Tyrode solution (37°C) containing 1 µM isoproterenol (Sigma, Catalogue No. : I6504), ex vivo ECG were continuously measured by placing recording electrodes around the heart as we previously described 20,46 (Figure 1E). PES was applied using a MyoPacer (IonOptix) via a pair of platinum electrodes placed on the left ventricular apex of the heart.…”

Section: Surface Ecg and Echocardiographymentioning

confidence: 99%

“…16,17 However, one study reported that increased Wnt/β-catenin signalling was only found in the myocardium of post-MI pigs with hypercholesterolemia, but not in post-MI pigs with normal cholesterol levels. 18 Recent studies, including those from our group, 19,20 have demonstrated the capability of Wnt/β-catenin signalling to regulate the expression of both Scn5a (encoding Na v 1.5) [19][20][21][22][23][24] and Gja1 (encoding Cx43), 24,25 which are critical for the myocardial conduction velocity and play roles in post-MI electrical remodeling and arrhythmogenesis. However, it remains unknown if Wnt/β-catenin signalling plays a role in the post-MI alterations in ion channel genes.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of β-catenin Protects Mouse Hearts From Ventricular Arrhythmias After Myocardial Infarction Independent of Ion Channel Gene Changes

Wang

Xia

et al. 2021

Preprint

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The Wnt/β-catenin signaling regulates ion channel gene expressions in cardiomyocytes. Because Wnt/β-catenin signaling is activated in myocardial infarction (MI), this study aims to investigate if β-catenin inhibition affects post-MI ion channel gene alterations and ventricular tachycardias (VT). MI was induced by permanent ligation of left anterior descending artery in wild-type (WT) and cardiomyocyte-specific β-catenin knockout (KO) mice. KO mice showed reduced susceptibility to VT (18% vs. 77% in WT) at week-8 after MI, associated with attenuated structural remodeling (reduced scar size and attenuated left ventricle dilation) as compared to WT. However, at the subacute phase (week-1) and chronic phase (week-8) after MI, Wnt/β-catenin signaling activation was found in non-cardiomyocytes, but not in cardiomyocytes. Downregulations of Scn5a (encoding Nav1.5) and Gja1 (encoding Cx43) were found at week-1 but not at week-8, while downregulations of K+ channel genes were present at both week-1 and -8. Consistent with no activation of Wnt/β-catenin pathway in cardiomyocytes at week-1 and -8, these alterations in ion channel/transporter genes were not different between KO and WT mice. This study demonstrated that mice with cardiomyocyte-specific β-catenin deletion have reduced VT susceptibility after MI which is caused by attenuated structural remodeling, instead of alterations in ion channel gene expressions.

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Genome Editing and Inherited Cardiac Arrhythmias

Lalaguna

Ramos-Hernández

Priori

et al. 2022

Advances in Experimental Medicine and Biology

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Direct and Indirect Suppression of Scn5a Gene Expression Mediates Cardiac Na+ Channel Inhibition by Wnt Signalling

Cited by 17 publications

References 46 publications

Cardiomyocyte-specific deletion of β-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction

Cardiomyocyte-specific deletion of β-catenin protects mouse hearts from ventricular arrhythmias after myocardial infarction

Inhibition of β-catenin Protects Mouse Hearts From Ventricular Arrhythmias After Myocardial Infarction Independent of Ion Channel Gene Changes

Genome Editing and Inherited Cardiac Arrhythmias

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