UC Davis

Chronic hyperglycemia and diabetes lead to impaired cardiac repolarization, K⁺ channel remodeling and increased arrhythmia risk. However, the exact signaling mechanism by which diabetic hyperglycemia regulates cardiac K⁺ channels remains elusive. Here, we show that acute hyperglycemia increases inward rectifier K⁺ current (I_K1), but reduces the amplitude and inactivation recovery time of the transient outward K⁺ current (I_to) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, I_K1 amplitude and I_to recovery effects (but not I_to amplitude) were prevented by the Ca²⁺/calmodulin-dependent kinase II (CaMKII) inhibitor autocamtide-2-related inhibitory peptide, CaMKIIδ-knockout, and O-GlcNAc-resistant CaMKIIδ-S280A knock-in. I_to reduction was prevented by inhibition of protein kinase C (PKC) and NADPH oxidase 2 (NOX2)-derived reactive oxygen species (ROS). In mouse models of chronic diabetes (streptozotocin, db/db, and high-fat diet), heart failure, and CaMKIIδ overexpression, both I_to and I_K1 were reduced in line with the downregulated K⁺ channel expression. However, I_K1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances I_K1 and I_to recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces I_to amplitude via a NOX2-ROS-PKC pathway. Moreover, chronic hyperglycemia during diabetes and CaMKII activation downregulate K⁺ channel expression and function, which may further increase arrhythmia susceptibility.