TY - JOUR
T1 - Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles
AU - Li, Gang
AU - Khandekar, Aditi
AU - Yin, Tiankai
AU - Hicks, Stephanie C.
AU - Guo, Qiusha
AU - Takahashi, Kentaro
AU - Lipovsky, Catherine E.
AU - Brumback, Brittany D.
AU - Rao, Praveen K.
AU - Weinheimer, Carla J.
AU - Rentschler, Stacey L.
N1 - Publisher Copyright:
© 2018 Elsevier Ltd
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
KW - Cardiac development
KW - Cardiac electrophysiology
KW - Connexin43
KW - Transcriptional regulation
KW - Wnt signaling, Ventricular tachycardia
UR - http://www.scopus.com/inward/record.url?scp=85053080447&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2018.09.002
DO - 10.1016/j.yjmcc.2018.09.002
M3 - Article
C2 - 30193957
AN - SCOPUS:85053080447
SN - 0022-2828
VL - 123
SP - 92
EP - 107
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -