New Insights Into the Role of GSK-3 in the Regulation of Human Cardiac Electrophysiology

C ardiac arrhythmias still represent a serious health issue, leading to adverse outcomes, such as heart failure and sudden death.Several drugs used to treat noncardiac diseases, including antibiotics or antipsychotics, can also be responsible for arrhythmia development.Therefore, a major challenge is a deeper comprehension of the molecular mechanisms regulating cardiac electrophysiology, together with the development of predictive tools aimed at understanding how a specific condition or drug can favor arrhythmic events.Glycogen synthase kinase-3 (GSK-3) is a serine/ threonine kinase regulating several cellular processes and signaling cascades in the heart.GSK-3 plays a pivotal role in heart pathophysiology in different stress conditions, such as pressure overload and ischemic injury, exerting both detrimental and protective effects in a context-dependent manner.GSK-3 represents one of the main components of the Wnt pathway.In the absence of the Wnt ligand, GSK-3 phosphorylates b-catenin, allowing its ubiquitination and degradation.When dephosphorylated, b-catenin accumulates in the cytoplasm and then translocates in the nucleus, where it acts as a transcription factor. 1 b-catenin also participates in the regulation of cell adhesion properties of cardiomyocytes, as it is a component of desmosomes and adherent junctions, which also represent important connections for propagating electrical impulses through the myocardial tissue.Previous work demonstrated that Wnt/b-catenin activation reduces cardiac conduction velocity, owing to the decreased activity of the major cardiac sodium channel subunit Na v 1.5 and of the gap junction isoforms connexin-40 and -43. 2 Other reports showed that pharmacological inhibition of GSK-3 with the molecule SB216763 prevents arrhythmias in animal models of arrhythmogenic cardiomyopathy.3 These data suggest that GSK-3 inhibition may reprogram cardiac electrophysiology by activating the Wnt/b-catenin pathway.In this issue of JACC: Basic to Translational Science, Li et al 4 investigated for the first time the effects of acute GSK-3 inhibition by means of the compound SB216763 (SB2) on cardiac conduction and electrophysiology in human hearts, by using a combined experimental and computational approach.They observed a reduction of impulse conduction velocity in human left ventricular slices obtained from nonfailing donor hearts subjected to acute treatment with SB2 (at 3 and 24 hours), along with a decreased action potential upstroke velocity, indicative of an altered excitability.These effects were associated with the reduction of Na v 1.5 protein levels, but with unaltered gene expression, suggesting the involvement of posttranscriptional mechanisms leading to decreased Na v 1.5 levels in response to acute GSK-3 inhibition.b-catenin protein levels were also found to be increased, along with its chromatin-bound nuclear accumulation, in response to SB2 treatment.By using a computational platform of virtual cardiac organotypic slices, the authors demonstrated that the decreased conduction velocity and action potential excitability are associated with reduced sodium channel conductance and tissue conductivity, consistently with the experimental data.