The Role of CaMKII Overexpression and Oxidation in Atrial Fibrillation-A Simulation Study.

Wei Wang,Yong Xu,Shanzhuo Zhang,Gongning Luo,Weijian Shen,Kuanquan Wang,Henggui Zhang

doi:10.3389/fphys.2020.607809

Abstract

This simulation study aims to investigate how the Calcium/calmodulin-dependent protein kinase II (CaMKII) overexpression and oxidation would influence the cardiac electrophysiological behavior and its arrhythmogenic mechanism in atria. A new-built CaMKII oxidation module and a refitted CaMKII overexpression module were integrated into a mouse atrial cell model for analyzing cardiac electrophysiological variations in action potential (AP) characteristics and intracellular Ca2+ cycling under different conditions. Simulation results showed that CaMKII overexpression significantly increased the phosphorylation level of its downstream target proteins, resulting in prolonged AP and smaller calcium transient amplitude, and impaired the Ca2+ cycling stability. These effects were exacerbated by extra reactive oxygen species, which oxidized CaMKII and led to continuous high CaMKII activation in both systolic and diastolic phases. Intracellular Ca2+ depletion and sustained delayed afterdepolarizations (DADs) were observed under co-existing CaMKII overexpression and oxidation, which could be effectively reversed by clamping the phosphorylation level of ryanodine receptor (RyR). We also found that the stability of RyR release highly depended on a delicate balance between the level of RyR phosphorylation and sarcoplasmic reticulum Ca2+ concentration, which was closely related to the genesis of DADs. We concluded that the CaMKII overexpression and oxidation have a synergistic role in increasing the activity of CaMKII, and the unstable RyR may be the key downstream target in the CaMKII arrhythmogenic mechanism. Our simulation provides detailed mechanistic insights into the arrhythmogenic effect of CaMKII overexpression and oxidation, which suggests CaMKII as a promising target in the therapy of atrial fibrillation.

Highlights

Atrial fibrillation (AF) is the most common persistent arrhythmia, affecting ∼33 million of the world’s population (Chugh et al, 2014), while the treatment of AF is difficult due to its selfreinforcing and structural remodeling properties
No significant impact of reactive oxygen species (ROS) can be observed on the action potential (AP) in neither the wild type (WT) nor the calmodulin-dependent protein kinase II (CaMKII)-OE model, which suggests that CaMKII oxidation has limited influence on membrane currents
Clamping simulations showed that this instability is highly related to the balance between the ryanodine receptor (RyR) phosphorylation and [Ca2+]sarcoplasmic reticulum (SR) level, which may be the underlying mechanism of the delayed afterdepolarizations (DADs) and AF induced by CaMKII hyperactivity

Summary

Introduction

Atrial fibrillation (AF) is the most common persistent arrhythmia, affecting ∼33 million of the world’s population (Chugh et al, 2014), while the treatment of AF is difficult due to its selfreinforcing and structural remodeling properties. The CaMKII dependent phosphorylation of phospholamban (PLB) increases the affinity of SR Ca2+-ATPase (SERCA) for Ca2+, leading to an enhancement of its Ca2+ transportation rate (Odermatt et al, 1996). In atria, sarcolipin can undergo CaMKII dependent phosphorylation, which influences SERCA and results in an increased SR uptake (Heijman et al, 2014). Besides these targets directly related to calcium cycling, CaMKII regulates other membrane currents, including INa, INaL, IKur, Ito, IK1, INCX, etc. The above-mentioned CaMKII regulation of downstream target proteins enables cardiomyocytes to adaptively enhance the speed of intracellular Ca2+ circulation when the heart rate increases, thereby continuously and effectively contracting at a higher heart rate

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