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. Reactive oxygen species (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 (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 show that T1D and T2D significantly increased AF, and this increase required CaMKII and OGN. T1D and T2D both require ox-CaMKII to increase AF, however we did not detect OGN-CaMKII nor 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 new and unanticipated insights into the mechanisms for increased AF in DM, and suggest potential benefits for future CaMKII and OGN targeted therapies.
About The Expert
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 Boronina
Robert N Cole
Lars S Maier
Xander Ht Wehrens
Joel L Pomerantz
Long-Sheng Song
Rexford Ahima
Gerald W Hart
Natasha E Zachara
Mark E Anderson
References
PubMed