Role of Oxidation-Dependent CaMKII Activation in the Genesis of Abnormal Action Potentials in Atrial Cardiomyocytes: A Simulation Study

Qince Li,Henggui Zhang,Haibo Sui,Na Zhao

doi:10.1155/2020/1597012

Abstract

Atrial fibrillation is a common cardiac arrhythmia with an increasing incidence rate. Particularly for the aging population, understanding the underlying mechanisms of atrial arrhythmia is important in designing clinical treatment. Recently, experiments have shown that atrial arrhythmia is associated with oxidative stress. In this study, an atrial cell model including oxidative-dependent Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII) activation was developed to explore the intrinsic mechanisms of atrial arrhythmia induced by oxidative stress. The simulation results showed that oxidative stress caused early afterdepolarizations (EADs) of action potentials by altering the dynamics of transmembrane currents and intracellular calcium cycling. Oxidative stress gradually elevated the concentration of calcium ions in the cytoplasm by enhancing the L-type Ca2+ current and sarcoplasmic reticulum (SR) calcium release. Owing to increased intracellular calcium concentration, the inward Na+/Ca2+ exchange current was elevated which slowed down the repolarization of the action potential. Thus, the action potential was prolonged and the L-type Ca2+ current was reactivated, resulting in the genesis of EAD. Furthermore, based on the atrial single-cell model, a two-dimensional (2D) ideal tissue model was developed to explore the effect of oxidative stress on the electrical excitation wave conduction in 2D tissue. Simulation results demonstrated that, under oxidative stress conditions, EAD hindered the conduction of electrical excitation and caused an unstable spiral wave, which could disrupt normal cardiac rhythm and cause atrial arrhythmia. This study showed the effects of excess reactive oxygen species on calcium cycling and action potential in atrial myocytes and provided insights regarding atrial arrhythmia induced by oxidative stress.

Highlights

IntroductionTo design optimal treatment of Atrial fibrillation (AF), the mechanisms underlying AF need to be better understood
Atrial fibrillation (AF) is the most common cardiac arrhythmia [1,2,3]
These results demonstrated an elevation in the repolarization phase of the AP and, a longer action potential duration (APD) in our model (Figure 3(a))

Summary

Introduction

To design optimal treatment of AF, the mechanisms underlying AF need to be better understood Both reactive oxygen species (ROS) and Ca2+/calmodulin- (CaM-) dependent protein kinase II (CaMKII) have been shown to be associated with the development of cardiac arrhythmias [4, 5]. The kinase CaMKII is ubiquitously expressed in the cardiomyocytes [4, 6] It is involved in numerous cellular signaling cascades, such as phosphorylation of L-type Ca2+ channels [7,8,9], Na+ channels [10, 11], ryanodine receptors (RyRs) [12,13,14,15,16,17,18], and phospholamban (PLB) [12, 17, 19, 20]. Phosphorylation of Ltype Ca2+ channels induced by CaMKII is associated with

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Discussion

Conclusion