Wnt-1 regulation of connexin43 in cardiac myocytes

Gap junction channels composed of connexin43 (Cx43) are essential for norma l heart formation and function. We studied the potential role of the Wnt fa mily of secreted polypeptides as regulators of Cx43 expression and gap junc tion channel function in dissociated myocytes and intact hearts. Neonatal r at cardiomyocytes responded to Li+, which mimics Wnt signaling, by accumula ting the effector protein beta-catenin and by inducing Cx43 mRNA and protei n markedly. Induction of Cx43 expression was also observed in cardiomyocyte s cocultured with Rat-2 fibroblasts or N2A neuroblastoma cells programmed t o secrete bioactive Wnt-1. By transfecting a Cx43 promoter-reporter gene co nstruct into cardiomyocytes, we demonstrated that the inductive effect of W nt signaling was transcriptionally mediated. Enhanced expression of Cx43 in creased cardiomyocyte cell coupling, as determined by Lucifer Yellow dye tr ansfer and by calcium wave propagation. Conversely in a transgenic cardiomy opathic mouse model that exhibits ventricular arrhythmias and gap junctiona l remodeling, beta-catenin and Cx43 expression were downregulated concordan tly. In response to Wnt signaling, the accumulating Cx43 colocalized with b eta-catenin in the junctional membrane; moreover, forced expression of Cx43 in cardiomyocytes reduced the transactivation potential of beta-catenin. T hese findings demonstrate that Wnt signaling is an important modulator of C x43-dependent intercellular coupling in the heart, and they support the hyp othesis that dysregulated signaling contributes to altered impulse propagat ion and arrhythmia in the myopathic heart.