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 5

Targeted ROS inhibition and MsrA overexpression protects against atrial fibrillation in diabetes.

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Targeted ROS inhibition and MsrA overexpression protects against atrial ...
(A) Inhibition of mitochondrial ROS by MitoTEMPO treatment or inhibition of cytoplasmic ROS by loss of the p47 subunit of NADPH oxidase (p47–/– mice) protect against AF in T1D mice. Mice with myocardial targeted transgenic overexpression of methionine sulfoxide reductase A (MsrA TG) were protected from T1D primed AF; nondiabetic mice lacking MsrA (MrsA–/– non-DM) showed increased AF susceptibility in the absence of diabetes. (B) Summary data of blood glucose measurements at the time of electrophysiology study. (C) Increased mitochondrial ROS in isolated atrial myocytes from WT T1D (bottom) compared with WT non-DM (top) mice detected by MitoSOX fluorescence. Representative confocal fluorescent images (original magnification, ×40) show MitoSOX (red, left), MitoTracker (green, middle), and merged images (right). Scale bars: 10 μm. (n = 41–47 cells in each group from 2 mice per group). Data are represented as percentage frequency distribution (A) and mean ± SEM (B and C). The numerals in the bars represent the sample size in each group (A). Statistical comparisons were performed using 2-tailed Fischer’s exact test with Holm-Bonferroni correction for multiple comparisons (A), 1-way ANOVA with Tukey’s multiple-comparison test (B) and 2-tailed Student’s t test (C). (*P < 0.05). WT T1D data set (A and B), control data previously presented. AF, atrial fibrillation; DM, diabetes mellitus; T1D, type 1 DM; T2D, type 2 DM.