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.
View: Text | PDF
Research Article Cardiology Article has an altmetric score of 7

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

×

Figure 6

Targeted OGN inhibition is protective against atrial fibrillation susceptibility in type 1 and type 2 diabetes.

Options: View larger image (or click on image) Download as PowerPoint
Targeted OGN inhibition is protective against atrial fibrillation suscep...
(A) DON pretreatment (5 mg/kg i.p.) protected from AF in T1D WT and S280A mice, with no additional protection in T1D MMVV mice. (B) DON pretreatment did not protect from AF in T2D WT mice. (C) Schematic of the OGA (O-GlcNAcase) transgene construct with the α-myosin heavy chain (α-MHC) promoter, HA epitope marker, and human growth hormone polyA signal (HGH1) (top). PCR product validation of OGA transgene expression in 2 founder pups (OGA-transgenic mice, OGA-TG). The line with the higher OGA expression was chosen for further experiments (bottom). (D) Western blot for OGA transgene and HA epitope expression in heart (H), gastrocnemius muscle (G), liver (L), and kidney (K) from WT and OGA-TG mice. (E) OGA-TG mice were protected from enhanced AF in T1D. (F) OGA-TG mice had similar blood glucose levels as WT littermates under T1D and nondiabetic conditions. (G) OGA-TG were protected from enhanced AF in T2D. (H) OGA-TG mice had similar blood glucose levels as WT T2D mice. DON, 6-diazo-5-oxo-L-norleucine; AF, atrial fibrillation; DM, diabetes mellitus; T1D, type 1 DM; T2D, type 2 DM. Data are represented as percentage frequency distribution (A, B, E, and G) and mean ± SEM (F and H). The numerals in the bars represent the sample size in each group (A, B, E, and G). Statistical comparisons were performed using 2-tailed Fischer’s exact test with Holm-Bonferroni correction for multiple comparisons (A, B, E, and G), 1-way ANOVA with Tukey’s multiple-comparison test (F and H). (*P < 0.05). WT T1D (A) and T2D (B, G, and H) data sets are control data previously presented.