# Wnt Signaling in Cardiac Conduction and Arrhythmogenesis

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2021 · $514,515

## Abstract

Project Summary
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 β-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 β-catenin accumulation in human left ventricular tissue from failing and non-failing hearts, and
determine whether nuclei with and without β-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.

## Key facts

- **NIH application ID:** 10119075
- **Project number:** 2R01HL130212-06A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** STACEY Lynn RENTSCHLER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $514,515
- **Award type:** 2
- **Project period:** 2016-01-01 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10119075

## Citation

> US National Institutes of Health, RePORTER application 10119075, Wnt Signaling in Cardiac Conduction and Arrhythmogenesis (2R01HL130212-06A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10119075. Licensed CC0.

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