Abstract
Abstract 459: Oxidized CaMKII Causes Atrial Fibrillation Susceptibility in a Diabetic Mouse Model
Circulation research, Vol.119(suppl_1)
07/22/2016
DOI: 10.1161/res.119.suppl_1.459
Abstract
Background:
Atrial fibrillation (AF) and diabetes mellitus (DM) are major, unsolved public health problems. DM is a known risk factor for AF, and both are associated with increased reactive oxygen species (ROS), suggesting a ROS responsive disease signal could be a mechanistic link between them. The multifunctional Ca2+ and calmodulin-dependent protein kinase-II (CaMKII) is activated by oxidation of paired methionines. Oxidized CaMKII (ox-CaMKII) is increased in atria from DM patients and causes ryanodine receptor (RyR2) hyperphosphorylation that promotes pathological intracellular Ca2+ release and Ca2+ triggered arrhythmias. We hypothesize that DM increases myocardial ox-CaMKII, RyR2 hyperphosphorylation and AF.
Methods and Results:
C57BL/6J mice with streptozocin-induced type 1 DM had increased AF susceptibility following atrial burst pacing compared with citrate buffer-treated wild-type (WT) controls [70% (14/20) vs. 25% (5/20), p = 0.01]. Ox-CaMKII was increased in atrial tissue from diabetic mice compared to controls, consistent with a role for ox-CaMKII in this model. Diabetic ox-CaMKII resistant knock-in (MM-VV) mice (37.5% (9/24) [p < 0.05]) and diabetic mice with myocardium-restricted transgenic overexpression of methionine sulfoxide reductase A (25% (5/20) [p < 0.05]), which reverses ox-CaMKII, were protected from DM increased AF susceptibility compared to diabetic WT controls. Atrial myocytes from diabetic WT mice demonstrated increased RyR2 mediated Ca2+ spark frequency, triggered action potentials and delayed intracellular [Ca2+] decay compared to controls. Diabetic knock-in mice resistant to CaMKII-mediated RyR2 phosphorylation (S2814A) had decreased AF susceptibility (25% (5/20) [p < 0.05]), compared with diabetic WT mice. All groups of diabetic mice had similar increases in plasma glucose.
Conclusions:
Hyperglycemia increases AF susceptibility and increased ox-CaMKII is associated with increased AF in this diabetic mouse model. Genetic manipulation of an ox-CaMKII pathway can protect against AF susceptibility in DM. These findings suggest that ox-CaMKII is a critical proarrhythmic signal in DM and a potential therapeutic target for AF management in DM patients.
Details
- Title: Subtitle
- Abstract 459: Oxidized CaMKII Causes Atrial Fibrillation Susceptibility in a Diabetic Mouse Model
- Creators
- Olurotimi O Mesubi - Johns Hopkins MedicineAdam G Rokita - Roy J. and Lucille A. Carver College of MedicineBiyi Chen - University of IowaLong-Sheng Song - University of IowaXander H Wehrens - Baylor College of MedicineMark E Anderson - Johns Hopkins Medicine
- Resource Type
- Abstract
- Publication Details
- Circulation research, Vol.119(suppl_1)
- DOI
- 10.1161/res.119.suppl_1.459
- ISSN
- 0009-7330
- eISSN
- 1524-4571
- Language
- English
- Date published
- 07/22/2016
- Academic Unit
- Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Biochemistry and Molecular Biology
- Record Identifier
- 9984297459702771
Metrics
4 Record Views