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

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 Ca 2+ /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.