Abstract
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 (H2O2) induced neonatal cardiac myocytes (NCM) injury. In our study, NCM, when exposed to H2O2, resulted in persistent activation of PKR due to NCM endogenous RNA. Inhibition of PKR by 2-aminopurine (2-AP) or siRNA protected against H2O2 induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H2O2 induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H2O2 induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H2O2 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 H2O2-induced injury by attenuating apoptosis and inflammation. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H2O2 to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.
Highlights
Protected against H2O2 induced apoptosis and injury
A great part of cardiomyocytes cell death occurs via the process of acute reperfusion phase due to the development of oxidative stress induced by the generation of reactive oxygen species (ROS), such as H2O21,2
We found RNA from untreated neonatal cardiac myocytes (NCM) was unable to activate PKR, RNA from H2O2 treated NCM resulted in phosphorylation of PKR
Summary
Protected against H2O2 induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H2O2 induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. A self-preservation mechanism existed in NCM that ADAR1 expression is induced by H2O2 to limit PKR activation simultaneously These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury. NFκB and NLRP3 inflammasome pathway are both important inflammatory signaling, and new targeted therapeutic strategies such as anti-NFκB and anti-NLRP3 inflammasome were explored[6,7,8] It is unclear how these inflammatory signaling molecules are coordinately regulated in myocardial reperfusion injury process. Protein kinase PKR is double-stranded RNA (dsRNA)-activated serine/threonine protein kinase inducible by interferon(IFN) It was first identified as a mediator of the antiproliferative and antiviral actions of interferon. Encountering infections, PKR can regulate or act in conjunction with major inflammatory signaling pathways that are implicated in myocardial ischemia reperfusion injury, including NFκB and inflammasome NLRP311–14. It is possible that ADAR1 modulate PKR activity in cardiac myocytes
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