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 2

ROS and O-GlcNAcylation are elevated in type 1 and type 2 diabetic hearts.

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ROS and O-GlcNAcylation are elevated in type 1 and type 2 diabetic heart...
(A) Representative confocal images (original magnification, ×40) and summary data for DHE fluorescence in mouse atrial tissue show increased ROS in T1D (top) and T2D (bottom). Scale bars: 10μm (n = 6 WT non-DM, n = 8 WT T1D, n = 4 WT non-DM, n = 4 WT T2D) (B) Representative Western blots and summary data for total OGN modified protein levels (OGN monoclonal antibody – RL2) normalized to tubulin and competition assay (RL2 + 500 mM GlcNAc) from heart lysates, from T1D (left) and T2D (right) (n = 3–7/group). OGN quantification excluded the noncompeted bands. DHE, dihydroethidium; DM, diabetes mellitus; T1D, type 1 DM; T2D, type 2 DM; OGN, O-GlcNAcylation. Data are represented as mean ± SEM. Statistical comparisons were performed using 2-tailed Student’s t test (A and B) (*P < 0.05 vs. WT non-DM).