@article{a5466a9945da453299b0cd26bcaf4aa9,
title = "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.",
author = "Mesubi, {Olurotimi O.} and Rokita, {Adam G.} and Neha Abrol and Yuejin Wu and Biyi Chen and Qinchuan Wang and Granger, {Jonathan M.} and Anthony Tucker-Bartley and Luczak, {Elizabeth D.} and Murphy, {Kevin R.} and Priya Umapathi and Banerjee, {Partha S.} and Boronina, {Tatiana N.} and Cole, {Robert N.} and Maier, {Lars S.} and Wehrens, {Xander H.} and Pomerantz, {Joel L.} and Song, {Long Sheng} and Ahima, {Rexford S.} and Hart, {Gerald W.} and Zachara, {Natasha E.} and Anderson, {Mark E.}",
note = "Funding Information: We are grateful to Jinying Yang for her assistance in maintaining mouse colonies and Gianna Bortoli for her assistance with neonatal cell isolation. We are also grateful to Djahida Bedja for performing the mouse echocardiograms. We thank Chip Hawkins and the Johns Hopkins University School of Medicine Transgenic Core Laboratory for their technical expertise in generating transgenic mice. We thank the Johns Hopkins University School of Medicine Mass Spectrometry and Proteomics Facility for technical assistance in the mass spectrometry studies. We also thank Teresa Ruggle, who produced the artwork. We are grateful to Howard Schulman for the gift of the CaMKII inhibitor AS105. This work was funded in part by NIH grants R35 HL140034 to MEA; R01-HL089598, R01-HL091947, and R01-HL117641 to XHW; T32-HL007227 to OOM and PU; and 5K12HL141952-03 to PU, in addition to the Foundation Leducq Career Development Award to AGR. This work was also supported by an American Heart Association (AHA) collaborative science award (17CSA33610107 to MEA and GWH) and an AHA grant (13EIA14560061 to XHW). LSM was supported by the Deutsche Forschungsgemeinschaft Ma 1982/5-1. A Synergy Award from Johns Hopkins University to MEA and GWH and the Johns Hopkins Medicine Discovery Fund also made this work possible. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = jan,
day = "19",
doi = "10.1172/JCI95747",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",
}