Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms
Olurotimi O. Mesubi, … , Natasha E. Zachara, Mark E. Anderson
Olurotimi O. Mesubi, … , Natasha E. Zachara, Mark E. Anderson
Published November 5, 2020
Citation Information: J Clin Invest. 2021;131(2):e95747. https://doi.org/10.1172/JCI95747.
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Research Article Cardiology

Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms

Abstract

Diabetes mellitus (DM) and atrial fibrillation (AF) are major unsolved public health problems, and diabetes is an independent risk factor for AF. However, the mechanism(s) underlying this clinical association is unknown. ROS and protein O-GlcNAcylation (OGN) are increased in diabetic hearts, and calmodulin kinase II (CaMKII) is a proarrhythmic signal that may be activated by ROS (oxidized CaMKII, ox-CaMKII) and OGN (OGN-CaMKII). We induced type 1 (T1D) and type 2 DM (T2D) in a portfolio of genetic mouse models capable of dissecting the role of ROS and OGN at CaMKII and global OGN in diabetic AF. Here, we showed that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both required ox-CaMKII to increase AF; however, we did not detect OGN-CaMKII or a role for OGN-CaMKII in diabetic AF. Collectively, our data affirm CaMKII as a critical proarrhythmic signal in diabetic AF and suggest ROS primarily promotes AF by ox-CaMKII, while OGN promotes AF by a CaMKII-independent mechanism(s). These results provide insights into the mechanisms for increased AF in DM and suggest potential benefits for future CaMKII and OGN targeted therapies.

Authors

Olurotimi O. Mesubi, Adam G. Rokita, Neha Abrol, Yuejin Wu, Biyi Chen, Qinchuan Wang, Jonathan M. Granger, Anthony Tucker-Bartley, Elizabeth D. Luczak, Kevin R. Murphy, Priya Umapathi, Partha S. Banerjee, Tatiana N. Boronina, Robert N. Cole, Lars S. Maier, Xander H. Wehrens, Joel L. Pomerantz, Long-Sheng Song, Rexford S. Ahima, Gerald W. Hart, Natasha E. Zachara, Mark E. Anderson

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Figure 4

MM281/282 but not S280 is critical for CaMKII activation in response to hyperglycemia.

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MM281/282 but not S280 is critical for CaMKII activation in response to ...
(A) Schematic of CaMKII kinase translocation reporter (CaMKII-KTR) assay. CaMKII-KTR traffics between the nucleus and cytoplasm and phosphorylation by CaMKII results in net translocation of the KTR to the cytosol. Cytosolic to nuclear fluorescent signal ratio is a measure of CaMKII activity. (B) Representative fluorescent micrographs of KTR transfected neonatal mouse cardiomyocytes at baseline and time, t = 18 hours after treatment. Cells from WT pups were incubated as indicated with 5.5 mM glucose (low glucose, n = 18 cells), 5.5 mM glucose + 24.5 mM mannitol (mannitol, n = 19 cells), 30 mM glucose (high glucose, n = 26 cells), high glucose + 2 mM N-acetyl cysteine (high glucose + NAC, n = 11 cells), or high glucose + 1 μM AS105 (a CaMKII inhibitor, n = 13 cells). Cells from MMVV (n = 15 cells) and S280A (n = 15 cells) pups were incubated with high glucose. Cells from WT pups at baseline and time, t = 20 minutes after treatment with 10 mM caffeine (n = 15 cells). Arrowheads indicate nuclei. (C) Summary data of the change in KTR cytosolic/nuclear ratio before and after treatments. Data are represented as mean ± SEM, and statistical comparisons were performed using 1-way ANOVA with Dunnett’s multiple-comparison test (*P < 0.05).