Hyperglycemia regulates cardiac K + channels via O -GlcNAc-CaMKII and NOX2-ROS-PKC pathways
- PDF / 12,010,414 Bytes
- 19 Pages / 595.276 x 790.866 pts Page_size
- 88 Downloads / 160 Views
ORIGINAL CONTRIBUTION
Hyperglycemia regulates cardiac K+ channels via O‑GlcNAc‑CaMKII and NOX2‑ROS‑PKC pathways Bence Hegyi1 · Johanna M. Borst1 · Logan R. J. Bailey1 · Erin Y. Shen1 · Austen J. Lucena1 · Manuel F. Navedo1 · Julie Bossuyt1 · Donald M. Bers1 Received: 3 October 2020 / Accepted: 11 November 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract 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 (IK1), but reduces the amplitude and inactivation recovery time of the transient outward K + current ( Ito) in mouse, rat, and rabbit myocytes. These changes were all critically dependent on intracellular O-GlcNAcylation. Additionally, IK1 amplitude and Ito recovery effects (but not Ito amplitude) were prevented by the C a2+/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 Ito and IK1 were reduced in line with the downregulated K+ channel expression. However, IK1 downregulation in diabetes was markedly attenuated in CaMKIIδ-S280A. We conclude that acute hyperglycemia enhances IK1 and I to recovery via CaMKIIδ-S280 O-GlcNAcylation, but reduces Ito 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. Keywords Potassium channels · CaMKII · ROS · Hyperglycemia · Diabetes Abbreviations 4-AP 4-Aminopyridine AIP Autocamtide-2-related inhibitory peptide ANF Atrial natriuretic factor BIM Bisindolylmaleimide CaMKII Ca2+/calmodulin-dependent kinase II DM Diabetes mellitus DON 6-Diazo-5-oxo-l-norleucine HBP Hexosamine biosynthetic pathway HF Heart failure HFD High-fat diet IKr Rapid delayed rectifier K+ current Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00395-020-00834-8) contains supplementary material, which is available to authorized users. * Donald M. Bers [email protected] 1
Department of Pharmacology, University of California Davis, 451 Health Sciences Drive, Davis, CA, USA
IKs Slow delayed rectifier K+ current IKslow Slowly inactivating K+ current IK1 Inward rectifier K+ current ISS Steady-state K+ current Ito Transient outward K+ current LFD Low-fat diet NOX2 NADPH oxidase 2 Myh7 β-Myosin heavy chain OE Overexpression O-GlcNAc O-Linked β-N-acetylglucosamine OGA O-GlcNAcase OGT O-GlcNAc trans
Data Loading...
