Abstract 18884: Ryanodine Receptor Hyperphosphorylation Induces Arrhythmias in Diabetes
Background: Type-2 diabetes (T2D) heightens the risk of heart failure, arrhythmias and sudden cardiac death, but the underlying mechanisms are poorly understood.
Hypothesis: Spontaneous Ca2+ release from the sarcoplasmic reticulum (i.e., SR Ca2+ leak) is elevated in T2D hearts and contributes to the triggering of ventricular arrhythmias.
Methods: We compared hearts from rats with late-onset T2D (HIP rats) that develop cardiac hypertrophy, diastolic and systolic dysfunction and ventricular tachyarrhythmias vs. control, non-diabetic rats.
Results: The frequency of spontaneous Ca2+ sparks was elevated in myocytes from HIP vs. non-diabetic rats (2.6±0.2 vs. 1.9±0.2 sparks/100 μm/s), despite a significant reduction in the SR Ca2+ content (the peak of caffeine-induced Ca2+ transient was 2.9±0.2 in HIP rat myocytes compared to 5.4±0.8 in control). This result indicates an augmented activity of SR Ca2+ release channels (ryanodine receptors, RyR) in HIP myocytes. RyR activity is closely regulated by several posttranslational modifications. Immunoblot analysis revealed increased RyR phosphorylation at the CaMKII site (by ~3-fold) but not at the PKA site in HIP rat hearts, without any differences in total RyR expression. Although HIP rat hearts show oxidative stress, RyR oxidation, measured as the amount of free thiol, was similar in HIP and control hearts. Furthermore, there were no differences in RyR O-GlcNAcylation between HIP and control hearts. CaMKII inhibition with 1 μM KN-93 dissipated the difference in Ca2+ spark frequency between HIP and control myocytes (1.7±0.3 vs. 1.6±0.3 sparks/100 μm/s). These data suggest that CaMKII-dependent RyR phosphorylation is the main mechanism underlying the enhanced SR Ca2+ leak in hearts from diabetic HIP rats. Larger SR Ca2+ leak resulted in an increased propensity for triggering spontaneous action potentials (5 out of 16 HIP myocytes; 0 out of 19 control myocytes). In agreement with increased spontaneous activity, the SR Ca2+ load needed for generating a depolarizing transient inward current was significantly lower in HIP vs. WT myocytes.
Conclusion: Our results highlight a possible association between altered RyR hyperphosphorylation, SR Ca2+ leak and ventricular arrhythmias in T2D hearts.
Author Disclosures: I. Popescu: None. G. Yin: None. S. Srodulski: None. X. Peng: None. F. Despa: None. S. Despa: None.
- © 2016 by American Heart Association, Inc.