Enhancement of β-catenin/T-cell factor 4 signaling causes susceptibility to cardiac arrhythmia by suppressing NaV1.5 expression in mice

Hu, Rong; Hu, Chaowei; Zhao, Limei; Sun, Lihua; Wang, Ning; Lu, Yan; Ye, Bo; Deb, Arjun; Li, Faqian; Xu, Haodong

doi:10.1016/j.hrthm.2019.05.015

Cited by 11 publications

(8 citation statements)

References 25 publications

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“…Our laboratory and others have previously shown that developmental chronic β-catenin stabilization in mouse cardiomyocytes results in up-regulation of the Wnt signaling pathway and down-regulation of Scn5a , together with reduced Na V 1.5 protein and sodium current density. 17 , 18 , 22 Therefore, we asked whether adult-induced, chronically increased β-catenin in cardiomyocytes, which partially recapitulates GSK-3–mediated pharmacologic effects, is proarrhythmic. To determine whether cardiac conduction is regulated by β-catenin levels, we used a tamoxifen-inducible mouse model to conditionally delete β-catenin exon 3 in cardiomyocytes of adult mice ( αMHC-MCM +/o /Ctnnb1 fl(ex3)/+ , β-catenin GOF), which prevents β-catenin degradation through loss of phosphorylation sites targeting the protein for ubiquitination.…”

Section: Resultsmentioning

confidence: 99%

“… 16 , 17 , 18 Specifically, both Scn5a , the gene encoding the major cardiac sodium-channel subunit Na V 1.5 (the pore-forming α-subunit protein of the voltage-gated cardiac sodium channel), and Gja1 , the gene encoding for cardiac gap junction connexin 43 (Cx43), are transcriptionally regulated by Wnt/β-catenin. 18 , 19 , 20 , 21 , 22 β-catenin is also involved in cell-cell adhesion at the adherens junctions, where it binds to N-cadherin. 23 , 24 It has been shown that β-catenin accumulates at the intercalated discs of hearts with hypertrophic cardiomyopathy and that GSK-3β is simultaneously decreased.…”

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confidence: 99%

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Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

Brumback

Huang

et al. 2022

JACC: Basic to Translational Science

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

Brumback

Huang

et al. 2022

JACC: Basic to Translational Science

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“…Likewise in AF, the activation of this pathway may be contributing to the exacerbated oxidative damage. Recently, it was also observed that the transcription factor TCF/Lef activated by β-catenin negatively regulates the expression of the Nav1.5 sodium channel, encoded by the SCN5a gene, in addition to modulating its kinetics, promoting tachycardia and ventricular fibrillation in animal model (Huo et al 2019) . Regarding the structural remodeling of the atria, Wnt/β-catenin regulates the transcription of genes related to fibrosis in AF and in several other fibrotic diseases (Lv et al 2019) .…”

Section: Discussionmentioning

confidence: 99%

Meta-analysis of Transcriptomic Data Reveals Pathophysiological Modules Involved with Atrial Fibrillation

Bueno

Recamonde‐Mendoza

2020

Mol Diagn Ther

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Atrial fibrillation (AF) is a complex disease and affects millions of people around the world. The biological mechanisms that are involved with AF are complex and still need to be fully elucidated. Therefore, we performed a meta-analysis of transcriptome data related to AF to explore these mechanisms aiming at more sensitive and reliable results. Public transcriptomic datasets were downloaded, analyzed for quality control, and individually pre-processed. Differential expression analysis was carried out for each individual dataset, and the results were meta-analytically aggregated using the r-th ordered p-value method. We analyzed the final list of differentially expressed genes through network analysis, namely topological and modularity analysis, and functional enrichment analysis. The meta-analysis of transcriptomes resulted in 589 differentially expressed genes, whose protein-protein interaction network presented 11 hubs-bottlenecks and four main identified functional modules. These modules were enriched for, respectively, 23, 54, 33, and 53 biological pathways involved with the pathophysiology of AF, especially with the disease's structural and electrical remodeling processes. Stress of the endoplasmic reticulum, protein catabolism, oxidative stress, and inflammation are some of the enriched processes. Among hubs-bottlenecks genes, which are highly connected and probably have a key role in regulating these processes, we found HSPA5 , ANK2 , CTNNB1 , and VWF . Further experimental investigation of our findings may shed light on the pathophysiology of the disease and contribute to the identification of new therapeutic targets and treatments.

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“…We discovered that that EGR1 was targeted by 53 TFs (ex; LMO2); DDX5 was targeted by 51 TFs (ex; MYCN); NCOA3 was targeted by 48 TFs (ex; SIN3B); STAT1 was targeted by 42 TFs (ex; IRF8); HIF1A was targeted by 40 TFs (ex; GATA1); RPS14 was targeted by 45 TFs (ex; RCOR3); RPL3 was targeted by 44 TFs (ex; DMRT1); RPS19 was targeted by 42 TFs (ex; GCH1 [81], LYST (lysosomal trafficking regulator) [82], PELI1 [83], EGR1 [84], SNX10 [85], CA2 [86], ZEB2 [87], HIF1A [88], PLA2G7 [89] [105], NFIA (nuclear factor I A) [106], CCR7 [107], PRDX2 [108], ADK (adenosine kinase) [109], TCF7 [110], LGALS3 [111], OLFM2 [112], HDAC11 [113] and ARPC1B [114] are significantly related to the atherosclerosis. Studies have revealed that KCNJ2 [115], TLR4 [116], JAK2 [117], TLR2 [118], EGR1 [119], GAB1 [120], ZBTB11 [121], BIN1 [122], TCF4 [123], PPP1R13L [124], TRPM4 [125], LGALS3 [126] and SNTA1 [127] plays a key role in cardiac arrhythmia. Recently, increasing evidence demonstrated that KCNJ2 [128], TLR4 [129], CYP2D6 [130], TLR2 [129], SNX10 [131], SIRT1 [132], PF4 [133], PCYT2 [134] and LGALS3 [135] were altered expression in atrial fibrillation.…”

Section: Construction Of the Tf-hub Gene Regulatory Networkmentioning

confidence: 99%

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

Vastrad¹,

Vastrad²

2023

Preprint

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Coronary artery disease (CAD) is the most common cardiovascular disorder and the leading cause of heart related deaths in world. Increasing molecular targets have been discovered for CAD and CAD - related complications prognosis and therapy. However, there is still an urgent need to identify novel biomarkers. Therefore, we evaluated biomarkers that might help the diagnosis and treatment of CAD and CAD related complications. We searched next generation sequencing (NGS) dataset (GSE202625) and identified differentially expressed genes (DEGs) by comparing CAD and normal control samples using DESeq2. Gene ontology (GO) and pathway enrichment analyses of the DEGs were performed using the g:Profiler online database. The protein protein interaction (PPI) network was plotted with IMEx interactome and visualized using Cytoscape. Module analysis of the PPI network was done using PEWCC1. MiRNA hub gene regulatory network and TF hub gene regulatory network analysis was performed to identify the hub genes, miRNAs and TFs. Receiver operating characteristic (ROC) curve analysis was used to predict the diagnostic effectiveness of the hub genes. A total of 118 DEGs (479 up regulated genes and 479 down regulated genes) were detected. The GO enrichment analysis indicated that the DEGs most significantly enriched in cellular response to stimulus and biosynthetic process. The REACTOME pathway enrichment analysis revealed that the DEGs were most significantly enriched in immune system and eukaryotic translation elongation. PPI network, modules, miRNA hub gene regulatory network and TF hub gene regulatory network analysis demonstrated that EGR1, SIRT1, STAT1, LRRK2, HIF1A, CSNK2B, RPS3, RPS2, RPS4X and HDAC11 were the hub genes. On the whole, the findings of this study enhance our understanding of the potential molecular mechanisms of CAD and CAD-related complications, and provide potential targets for further research.

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Enhancement of β-catenin/T-cell factor 4 signaling causes susceptibility to cardiac arrhythmia by suppressing NaV1.5 expression in mice

Cited by 11 publications

References 25 publications

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

Acute Glycogen Synthase Kinase-3 Inhibition Modulates Human Cardiac Conduction

Meta-analysis of Transcriptomic Data Reveals Pathophysiological Modules Involved with Atrial Fibrillation

Identification of novel prognostic targets in coronary artery disease and related complications using bioinformatics and next generation sequencing data analysis

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