Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles

Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how...

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Published inJournal of molecular and cellular cardiology Vol. 123; pp. 92 - 107
Main Authors Li, Gang, Khandekar, Aditi, Yin, Tiankai, Hicks, Stephanie C., Guo, Qiusha, Takahashi, Kentaro, Lipovsky, Catherine E., Brumback, Brittany D., Rao, Praveen K., Weinheimer, Carla J., Rentschler, Stacey L.
Format Journal Article
LanguageEnglish
Published England Elsevier Ltd 01.10.2018
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ISSN0022-2828
1095-8584
1095-8584
DOI10.1016/j.yjmcc.2018.09.002

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Summary:Several inherited arrhythmias, including Brugada syndrome and arrhythmogenic cardiomyopathy, primarily affect the right ventricle and can lead to sudden cardiac death. Among many differences, right and left ventricular cardiomyocytes derive from distinct progenitors, prompting us to investigate how embryonic programming may contribute to chamber-specific conduction and arrhythmia susceptibility. Here, we show that developmental perturbation of Wnt signaling leads to chamber-specific transcriptional regulation of genes important in cardiac conduction that persists into adulthood. Transcriptional profiling of right versus left ventricles in mice deficient in Wnt transcriptional activity reveals global chamber differences, including genes regulating cardiac electrophysiology such as Gja1 and Scn5a. In addition, the transcriptional repressor Hey2, a gene associated with Brugada syndrome, is a direct target of Wnt signaling in the right ventricle only. These transcriptional changes lead to perturbed right ventricular cardiac conduction and cellular excitability. Ex vivo and in vivo stimulation of the right ventricle is sufficient to induce ventricular tachycardia in Wnt transcriptionally inactive hearts, while left ventricular stimulation has no effect. These data show that embryonic perturbation of Wnt signaling in cardiomyocytes leads to right ventricular arrhythmia susceptibility in the adult heart through chamber-specific regulation of genes regulating cellular electrophysiology. •Embryonic programming via canonical Wnt signaling regulates electrophysiology.•There is differential enhancer binding and activity in developing ventricles.•Hey2 is a direct Wnt target in the right ventricle only.•Wnt loss of function affects connexin43 and conduction in the right ventricle.•Wnt loss of function mice have susceptibility to ventricular tachycardia.
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ISSN:0022-2828
1095-8584
1095-8584
DOI:10.1016/j.yjmcc.2018.09.002