O-GlcNAcylation of cardiac Nav1.5 contributes to the development of arrhythmias in diabetic hearts

Background: Cardiovascular complications are major causes of mortality and morbidity in diabetic patients. The mechanisms underlying the progression of diabetic heart (DH) to ventricular arrhythmias are unclear. O-linked GlcNAcylation (O-GlcNAc) is a reversible post-translational modification for the regulation of diverse cellular processes. The purpose of this study was to assess whether the cardiac voltage-gated sodium channel (Nav1.5) is subjected to O-linked GlcNAcylation (O-GlcNAc), which plays an essential role in DH-induced arrhythmias. Methods and results: In this study, Sprague-Dawley rats (male, 200-230 g) were treated with a single high-dose of streptozotocin (STZ, 80mg/kg) to generate a ratmodel of diabetes. STZ-induced 3-month diabetic rats displayed increased susceptibility to ventricular arrhythmias. The elevated O-GlcNAc modification was correlated with decreases in both total and cytoplasmic Nav1.5 expression in vivo and in vitro. In addition, both co-immunoprecipitation and immunostaining assays demonstrated that hyperglycemia could increase the O-GlcNAc-modified Nav1.5 levels and decrease the interaction between Nav1.5 and Nav1.5-binding proteins Nedd4-2/SAP-97. Furthermore, patch-clamp measurements in HEK-293 T cells showed that Nav1.5 current densities decreased by 30% after high-glucose treatment, and the sodium currents increased via O-GlcNAc inhibition. Conclusion: Our data suggested that hyperglycemia increased the O-GlcNAc modification of Nav1.5 expression and decreased the interaction between Nav1.5 and Nedd4-2/SAP-97, which led to the abnormal expression and distribution of Nav1.5, loss of function of the sodium channel, and prolongation of the PR/QT interval. Excessive O-GlcNAc modification of Nav1.5 is a novel signaling event, which may be an underlying contributing factor for the development of the arrhythmogenesis in DH. (c) 2017 Published by Elsevier B.V.