RIP3/CaMK II-Mediated Cardiomyocyte Necroptosis Plays a Key Role in Coxsackievirus B3-Induced Acute Severe Myocarditis

Abstract Recent studies have shown that RIP3/CaMK II plays a key role in myocardial ischemia-reperfusion injury; however, the role of RIP3/CaMK II-mediated cardiomyocyte necroptosis in CVB3-induced severe myocarditis has remained largely unknown. In this study, we found that KN-93(CaMK II–specific inhibitor) significantly reduced myocardial cell necrosis, improved cardiac function, and an improved survival curve. To further understand the mechanisms behind the regulation of necroptosis by RIP3/CaMK II, we added Ti(reactive oxygen species–specific inhibitor) in the model using the double-antibody sandwich immunoassay and BCA methods. After adding Ti, H2O2 content in the CVB3+KN-93+Ti group was slightly lower than that in the CVB3+KN-93 group. However, there was no obvious improvement of cardiac function or survival curve. Collectively, the RIP3/CaMK II pathway plays a significant role in cardiomyocyte death induced by viral infection. KN-93 blocks this pathway and may serve as a new therapeutic option for the treatment of severe viral myocarditis. The mechanism may occur through the direct inhibition of CaMK II and the indirect inhibition of reactive oxygen species.