O-Glycosylation of Camkii at Serine 280 Promotes Cardiac Arrhythmias in Diabetic Hyperglycemia

Abstract

Diabetic cardiomyopathy is associated with increased arrhythmia risk. However, the exact molecular details in signaling and arrhythmia mechanisms remain incompletely understood. We measured action potentials (APs) in isolated murine ventricular myocytes exposed to high glucose (30 mM) versus control (5.5 mM glucose+24.5 mM mannitol to match osmolarity). Acute hyperglycemia prolonged AP duration, increased delayed afterdepolarizations and inducibility of AP-duration alternans during tachypacing. These effects were prevented by OSMI-1, a selective inhibitor of O-GlcNAc transferase (preventing O-GlcNAcylation), and enhanced by thiamet-G, a selective O-GlcNAcase inhibitor (that should promote O-GlcNAcylation). Thus, O-GlcNAcylation is necessary and sufficient for these arrhythmogenic alterations. These effects were also prevented in CaMKIIδ-knockout myocytes and in mice in which a known O-GlcNAcylated Serine on CaMKII was mutated (S280A knock-in). In streptozotocin-induced diabetes, myocytes bathed in normal (5.5 mM) glucose exhibited prolonged AP duration, enhanced delayed afterdepolarizations and alternans, all of which were worsened by acute hyperglycemia. Premature ventricular complexes on electrocardiograms were enhanced in diabetic WT but not in CaMKIIδ-knockout animals. Moreover, the arrhythmogenic remodeling in diabetes was abolished by the CaMKII inhibitor AIP or in S280A mice. We conclude that O-GlcNAcylation of CaMKII at Serine 280 enhances cardiac arrhythmias and represents a significant, novel therapeutic target in diabetes.