Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms

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 cal...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-01, Vol.131 (2), p.1-14
Main Authors: Mesubi, Olurotimi O, Rokita, Adam G, Abrol, Neha, Wu, Yuejin, Chen, Biyi, Wang, Qinchuan, Granger, Jonathan M, Tucker-Bartley, Anthony, Luczak, Elizabeth D, Murphy, Kevin R, Umapathi, Priya, Banerjee, Partha S, Boronina, Tatiana N, Cole, Robert N, Maier, Lars S, Wehrens, Xander H, Pomerantz, Joel L, Song, Long-Sheng, Ahima, Rexford S, Hart, Gerald W, Zachara, Natasha E, Anderson, Mark E
Format: Article
Language:English
Subjects:
Acylation
Animal models
Animals
Atrial Fibrillation - enzymology
Atrial Fibrillation - genetics
Biomedical research
Ca2+/calmodulin-dependent protein kinase II
Calcium-binding protein
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism
Calmodulin
Cardiac arrhythmia
Cardiomyopathy
Diabetes
Diabetes Complications - enzymology
Diabetes Complications - genetics
Diabetes mellitus
Diabetes Mellitus, Experimental - enzymology
Diabetes Mellitus, Experimental - genetics
Diabetes Mellitus, Type 1 - enzymology
Diabetes Mellitus, Type 1 - genetics
Diabetes Mellitus, Type 2 - enzymology
Diabetes Mellitus, Type 2 - genetics
Fibrillation
Glucose
Heart
Hyperglycemia
Hypotheses
Insulin resistance
Kinases
Mice
Mice, Knockout
Mortality
O-GlcNAcylation
Oxidation-Reduction
Proteins
Public health
Risk factors
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI95747