Key points: Wnt signalling is activated in arrhythmogenic heart diseases, but its role in the regulation of cardiac ion channel expression is unknown. Exposure of neonatal rat ventricular myocytes to Wnt3a, an activator of canonical Wnt signalling, decreases Scn5a mRNA, Nav1.5 protein and Na+ current density. Wnt3a does not affect the inward rectifier K+ current or L-type Ca2+ channels. The Wnt pathway is a negative regulator of cardiac Na+ channel expression and may play a role in altered ion channel expression in heart disease. Wnt signalling plays crucial roles in heart development, but is normally suppressed postnatally. In arrhythmogenic conditions, such as cardiac hypertrophy and heart failure, Wnt signalling is reactivated. To explore the potential role of Wnt signalling in arrhythmogenic electrical remodelling, we examined voltage-dependent ion channels in cardiomyocytes. Treatment of neonatal rat ventricular myocytes with either recombinant Wnt3a protein or CHIR-99021 (CHIR, a glycogen synthase kinase-3β inhibitor) caused a dose-dependent increase in Wnt target gene expression (Axin2 and Lef1), indicating activation of the Wnt/β-catenin pathway. Cardiac Na+ current (INa) density was reduced by Wnt3a (-20 ± 4 vs. control -59 ± 7 pA pF-1, at -30 mV) or CHIR (-22 ± 5 pA pF-1), without changes in steady-state activation, inactivation or repriming kinetics. Wnt3a and CHIR also produced dose-dependent reductions in the mRNA level of Scn5a (the cardiac Na+ channel α subunit gene), as well as a 56% reduction (by Wnt3a) in the Nav1.5 protein level. Consistent with INa reduction, action potentials in Wnt3a-treated neonatal rat ventricular myocytes had a lower upstroke amplitude (91 ± 3 vs. control 137 ± 2 mV) and decreased maximum upstroke velocity (70 ± 10 vs. control 163 ± 15 V s-1). In contrast, inward rectifier K+ current and L-type Ca2+ channels were not affected by Wnt3a treatment. Taken together, our data indicate that the Wnt/β-catenin pathway suppresses INa in postnatal cardiomyocytes and may contribute to ion channel remodelling in heart disease.
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