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Hyperglycemia regulates cardiac K+ channels via O-GlcNAc-CaMKII and NOX2-ROS-PKC pathways
Ist Teil von
Basic research in cardiology, 2020-12, Vol.115 (6), p.71-71, Article 71
Ort / Verlag
Berlin/Heidelberg: Springer Berlin Heidelberg
Erscheinungsjahr
2020
Quelle
Alma/SFX Local Collection
Beschreibungen/Notizen
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.