Introduction: Calcium/calmodulin-dependent protein kinase II (CaMKII) plays an important role in regulating excitation-contraction coupling in the cardiac myocyte. It has been reported increased reactive oxygen species (ROS) can oxidize CaMKII then improve its activity, and disrupt calcium cycling in the heart. However, the detailed influences of the oxidative CaMKII on mouse atria have not been fully elucidated.
Method: Based on a previous CaMKII model with the autophosphorylation pathway, we integrated an oxidation pathway into it and further incorporated this new CaMKII activation model into a mouse atria model. We did simulations with and without ROS at different pacing frequencies and analyzed AP characteristics, intracellular Ca2+ concentrations and SR Ca2+ fluxes. Furthermore, a burst pacing protocol was used to induce irregular behaviours of myocytes for investigating the reactions of CaMKII under oxidative stress.
Results: Simulations revealed the role of increased ROS in the prolongation of APD, the decrease in the AP amplitude and dV/dtmax. ROS increased the activity of CaMKII, but the improvement was only significant during the diastolic period. Among all the CaMKII-dependent phosphorylation targets, LTCC increased most significantly, while other targets had limited variations. No substantial differences were found on the level of intracellular Ca2+ concentration, but the Ca2+ transient was enlarged, showing stronger cardiac contraction under oxidative stress. DADs were observed after a burst pacing protocol, which cannot last for a long time. In our simulations, simply oxidation of CaMKII did not have a great impact on DADs, but DADs persisted for a longer time with increased CaMKII amount.
Conclusion: In this study, we constructed a new CaMKII activation model including the oxidation pathway for investigating the role of oxidative stress in myocytes. Our simulation provides detailed mechanistic insights into the influence of increased ROS, and how it further affects cardiac calcium cycling.