Journal article
Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms
The Journal of clinical investigation, Vol.131(2), pp.1-14
01/19/2021
DOI: 10.1172/JCI95747
PMCID: PMC7810480
PMID: 33151911
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.
Details
- Title: Subtitle
- Oxidized CaMKII and O-GlcNAcylation cause increased atrial fibrillation in diabetic mice by distinct mechanisms
- Creators
- Olurotimi O. Mesubi - Johns Hopkins MedicineAdam G. Rokita - Roy J. and Lucille A. Carver College of MedicineNeha Abrol - Johns Hopkins MedicineYuejin Wu - Johns Hopkins MedicineBiyi Chen - Roy J. and Lucille A. Carver College of MedicineQinchuan Wang - Johns Hopkins MedicineJonathan M. Granger - Johns Hopkins MedicineAnthony Tucker-Bartley - Johns Hopkins MedicineElizabeth D. Luczak - Johns Hopkins UniversityKevin R. Murphy - Johns Hopkins MedicinePriya Umapathi - Johns Hopkins MedicinePartha S. Banerjee - Johns Hopkins MedicineTatiana N. Boronina - Johns Hopkins MedicineRobert N. Cole - Johns Hopkins MedicineLars S. Maier - University Hospital RegensburgXander H. Wehrens - Baylor College of MedicineJoel L. Pomerantz - Johns Hopkins MedicineLong-Sheng Song - Roy J. and Lucille A. Carver College of MedicineRexford S. Ahima - Johns Hopkins UniversityGerald W. Hart - Johns Hopkins MedicineNatasha E. Zachara - Johns Hopkins MedicineMark E. Anderson - Johns Hopkins Medicine
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.131(2), pp.1-14
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI95747
- PMID
- 33151911
- PMCID
- PMC7810480
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 15
- Grant note
- R35 HL140034; R01-HL089598; R01-HL091947; R01-HL117641; T32-HL007227; 5K12HL141952-03 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA 13EIA14560061 / AHA grant Foundation Leducq Career Development Award Johns Hopkins Medicine Discovery Fund Ma 1982/5-1 / Deutsche Forschungsgemeinschaft; German Research Foundation (DFG) Johns Hopkins University 17CSA33610107 / American Heart Association (AHA) collaborative science award; American Heart Association
- Language
- English
- Date published
- 01/19/2021
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Internal Medicine
- Record Identifier
- 9984293080802771
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