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 1

Proposed CaMKII posttranslational modifications and type 1 and type 2 diabetic models.

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Proposed CaMKII posttranslational modifications and type 1 and type 2 di...
(A) Oxidation at methionines 281/282 and OGN at serine 280 are posttranslational modifications hypothesized to promote diabetic heart disease and arrhythmias. (B) Schematic representation of proposed hypothesis that excessive ROS and OGN in diabetes mellitus (DM) promotes AF through CaMKII-dependent signaling. (C) Schematic of diabetes induction and experimental protocol for T1D. Summary data for (D) blood glucose and (E) body weight in nondiabetic and T1D mice 2 weeks after STZ injection. (F) Schematic of DM induction and experimental protocol for T2D. Summary data for (G) blood glucose and (H) body weight in nondiabetic and T2D mice 2 weeks after LD-STZ injection. T1D, type 1 DM; T2D, type 2 DM; HFD, high-fat diet; LD-STZ, low-dose STZ; NCD, normal chow diet; OGN, O-GlcNAcylation; RyR2, ryanodine receptor type 2; STZ, streptozocin. Data are represented as mean ± SEM. Statistical comparisons were performed using 1-way ANOVA with Tukey’s multiple-comparison test (D, E, G, and H) (#P < 0.0001 vs. WT non-DM, *P < 0.05 vs. WT non-DM).