Background: The canonical Wnt/β-catenin pathway is activated in a variety of heart diseases, such as myocardial infarction and cardiac hypertrophy, that are associated with altered ion channel expressions and increased risk of cardiac arrhythmias. Previous work from our lab has demonstrated that the Wnt/β-catenin signalling (Wnt signalling) inhibits sodium (Na+) current in rat cardiomyocytes. In this project, we aim to investigate the mechanisms that underlie the inhibition of Na+ current by Wnt signalling in both rat and human cardiomyocytes.
Results: In both neonatal rat ventricular myocytes (NRVMs) and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), activation of the Wnt/β-catenin signalling led to reduced level of Na+ channel gene transcript (Scn5a), channel protein (Nav1.5) and channel current density. This suggests that reduced Scn5a expression is likely the primary mechanism for reduced Na+ current. In addition, we found that activation of the Wnt/β-catenin signalling in both NRVMs and iPSC-CMs upregulated Tbx3 transcript and protein levels, which is a transcription factor that is known to suppress Scn5a transcription. In NRVMs, siRNA-mediated Tbx3 knockdown attenuated (by ~30%) Wnt-induced reductions in Scn5a and Nav1.5 levels.
Conclusions: Our findings are consistent with the conclusion that Wnt/β-catenin signalling inhibits Na+ current in both rat and human cardiomyocytes by reducing Scn5a levels, with Tbx3 as one of the mediators.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/43727 |
| Date | 23 June 2022 |
| Creators | Chu, Cencen |
| Contributors | Liang, Wenbin |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
| Format | application/pdf |
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