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 3

CaMKII promotes enhanced atrial fibrillation susceptibility in type 1 and type 2 diabetic mice.

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CaMKII promotes enhanced atrial fibrillation susceptibility in type 1 an...
(A) Representative tracings of intracardiac (atrial, A-EGM; ventricular, V-EGM) and lead II surface electrocardiograms recorded immediately after rapid atrial burst pacing demonstrating normal sinus rhythm in a control non-DM WT mouse and irregular atrial and ventricular electrical impulses marking AF in a diabetic WT T1D mouse. (B) Marked AF susceptibility in WT T1D mice compared with WT non-DM mice. This is reversed in AC3-I and MMVV T1D mice, but not in S280A T1D mice. (C) Pre- and post-insulin pump (LinBit) implantation blood glucose levels 1 week after STZ treatment (pre-insulin pump) and 1 week after insulin pump implantation (post-insulin) (n = 22). (D) Insulin treatment prevents enhanced AF in WT T1D mice with blood glucose (BG) level less than 300 mg/dL on insulin treatment. (E) Increased AF susceptibility is present in WT T2D mice compared with nondiabetic controls; AC3-I and MMVV T2D mice are protected from enhanced AF, but there is no protection in S280A T2D mice. AF, atrial fibrillation; DM, diabetes mellitus; T1D, type 1 DM; T2D, type 2 DM; EGM, electrogram. Data are represented as percentage frequency distribution (B, D, and E) and mean ± SEM (C). The numerals in the bars represent the sample size in each group (B, D, and E). Statistical comparisons were performed using 2-tailed Fischer’s exact test with Holm-Bonferroni correction for multiple comparisons (B, D, and E) and 2-tailed Student’s t test (C) (*P < 0.05).