| First Author | Hegyi B | Year | 2020 |
| Journal | Basic Res Cardiol | Volume | 115 |
| Issue | 6 | Pages | 71 |
| PubMed ID | 33237428 | Mgi Jnum | J:355607 |
| Mgi Id | MGI:7750968 | Doi | 10.1007/s00395-020-00834-8 |
| Citation | Hegyi B, et al. (2020) Hyperglycemia regulates cardiac K(+) channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways. Basic Res Cardiol 115(6):71 |
| abstractText | 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, CaMKIIdelta-knockout, and O-GlcNAc-resistant CaMKIIdelta-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 CaMKIIdelta 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 CaMKIIdelta-S280A. We conclude that acute hyperglycemia enhances I(K1) and I(to) recovery via CaMKIIdelta-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. |
