Development of a novel Markov chain model for oxidative-dependent CaMKII? activation

Dysfunction in the Calcium (Ca²⁺)-calmodulin (CaM) dependent kinase II (CaMKII) signalling can lead to several pathologies, such as heart failure and arrhythmia. Especially, the role of CaMKII signalling in oxidative stress-induced arrhythmias remains unclear. In this study, we aimed to develop a new Markov chain model of CaMKII δ-isoform (CaMKIId) that involves both of the autophosphorylation and oxidation pathways to better simulate CaMKII signalling under oxidative stress in cardiomyocytes. Based on the four-state model developed by Chiba et al., we implemented two oxidized states including a Ca²⁺/CaM-bound state and a Ca²⁺/CaM-dissociated state, representing the new pathway of oxidation-dependent activation. Using the model, we reproduced the CaM affinity to CaMKIIδ, the dependence of autophosphorylation on CaM. The frequency-dependent activation of CaMKII was simulated for both CaMKII α- and δ-isoforms. For the oxidation pathway, our simulation suggested that H₂O₂ increased the kinase activity in a dose-dependent manner, which also fitted to experimental data. Finally this model was incorporated in a human atrial cell model to simulate the effects of CaMKII activation on cellular action potentials.