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

Abstract

BackgroundCardiovascular 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 resultsIn this study, Sprague-Dawley rats (male, 200-230 g) were treated with a single high-dose of streptozotocin (STZ, 80 mg/kg) to generate a rat model 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. ConclusionOur 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.