Inhibition of PKR protects against H(2)O(2)-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation

Reactive oxygenation species (ROS) generated from reperfusion results in cardiac injury through apoptosis and inflammation, while PKR has the ability to promote apoptosis and inflammation. The aim of the study was to investigate whether PKR is involved in hydrogen peroxide (H(2)O(2)) induced neonatal cardiac myocytes (NCM) injury. In our study, NCM, when exposed to H(2)O(2), resulted in persistent activation of PKR due to NCM endogenous RNA. Inhibition of PKR by 2-aminopurine (2-AP) or siRNA protected against H(2)O(2) induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H(2)O(2) induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H(2)O(2) induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H(2)O(2) treatment through STAT-2 dependent pathway. By gain and loss of ADAR1 expression, we confirmed ADAR1 modulated PKR activity. Therefore, we concluded inhibition of PKR protected against H(2)O(2)-induced injury by attenuating apoptosis and inflammation. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H(2)O(2) to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.