The Wnt signaling pathway regulates cardiac morphogenesis and has been associated with congenital heart disease in both mice and humans. Given that congenital heart diseases are often associated with ventricular arrhythmias, a common cause of morbidity and mortality in this patient population, a better understanding of the molecular basis may ultimately improve diagnostic and therapeutic options. We found that many genes encoding ion channel subunits are Wnt transcriptional targets during development, including the major sodium channel and gap junction isoforms expressed in the heart. Loss of Wnt signaling leads to changes in cardiac conduction that predispose mice to ventricular tachycardia originating from the right ventricle, even in the absence of a structural heart defect. Interestingly, global transcriptional changes are highly distinct between the left and right ventricles in Wnt loss of function mice, paralleling the distinct electrophysiologic changes. This proposal will seek to elucidate genomic regulatory elements responsible for differential right versus left ventricular transcriptional changes in the setting of Wnt perturbation. We hypothesize that non-coding genomic elements directing ventricular-specific expression patterns may underlie inherited arrhythmias such as Brugada syndrome and arrhythmogenic cardiomyopathy which primarily affect the right ventricle. Specifically, the first aim will elucidate the underlying mechanism whereby Wnt signaling regulates Hey2 expression in the murine right ventricle, and Notch signaling regulates Hey2 expression in the left ventricle, using transgenic approaches. Given that genome wide association studies have linked non-coding variants near HEY2 with Brugada syndrome, perturbation of regulatory elements responsive to Wnt and Notch may have relevance to human disease. Wnt signaling is also dysregulated in adult acquired heart diseases such as heart failure, a major cause of morbidity and mortality, where much less is known about its role in regulating conduction and arrhythmia susceptibility.
In Aim 2, we will determine whether there are changes in nuclear ?-catenin accumulation, the effector of canonical Wnt signaling, and whether it correlates with conduction changes in a clinically relevant murine heart failure model. As a step towards translation, we will measure Wnt activity and nuclear ?-catenin accumulation in human left ventricular tissue from failing and non-failing hearts, and determine whether nuclei with and without ?-catenin express distinct transcripts. Finally, Aim 3 will determine whether several clinically relevant GSK3 inhibitors inhibit sodium channel transcription in vitro and modulate conduction velocity in vivo.
This project addresses several issues of central importance to the understanding of congenital and acquired arrhythmias, significant causes of morbidity and mortality. This proposal tests the hypothesis that Wnt signaling transcriptionally regulates the expression of ion channel subunits that regulate cardiac conduction. The results and broad conclusions will be directly relevant to understanding the genetic basis of cardiac arrhythmias, and will aid in designing more effective diagnostic and therapeutic options for ventricular tachycardia.
| Li, Gang; Khandekar, Aditi; Yin, Tiankai et al. (2018) Differential Wnt-mediated programming and arrhythmogenesis in right versus left ventricles. J Mol Cell Cardiol 123:92-107 |
| Qiao, Yun; Lipovsky, Catherine; Hicks, Stephanie et al. (2017) Transient Notch Activation Induces Long-Term Gene Expression Changes Leading to Sick Sinus Syndrome in Mice. Circ Res 121:549-563 |
| Kang, C; Brennan, J A; Kuzmiak-Glancy, S et al. (2016) Technical advances in studying cardiac electrophysiology - Role of rabbit models. Prog Biophys Mol Biol 121:97-109 |
| Díaz-Trelles, Ramón; Scimia, Maria Cecilia; Bushway, Paul et al. (2016) Notch-independent RBPJ controls angiogenesis in the adult heart. Nat Commun 7:12088 |
| Khandekar, Aditi; Springer, Steven; Wang, Wei et al. (2016) Notch-Mediated Epigenetic Regulation of Voltage-Gated Potassium Currents. Circ Res 119:1324-1338 |
