Hyperglycemia regulates cardiac K + channels via O -GlcNAc-CaMKII and NOX2-ROS-PKC pathways

摘要: Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K+ channel remodeling increased arrhythmia risk. However, the exact signaling mechanism by which diabetic regulates channels remains elusive. Here, we show that acute increases inward rectifier current (IK1), but reduces amplitude inactivation recovery time of transient outward (Ito) in mouse, rat, rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, IK1 Ito effects (but not amplitude) prevented Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, O-GlcNAc-resistant CaMKIIδ-S280A knock-in. reduction was inhibition protein C (PKC) NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models chronic (streptozotocin, db/db, high-fat diet), heart failure, CaMKIIδ overexpression, both reduced line with downregulated expression. downregulation markedly attenuated CaMKIIδ-S280A. We conclude enhances via CaMKIIδ-S280 O-GlcNAcylation, a NOX2-ROS-PKC pathway. Moreover, during CaMKII activation downregulate expression function, may further increase susceptibility.