Inhibition of PKR protects against H2O2-induced injury on neonatal cardiac myocytes by attenuating apoptosis and inflammation

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.

The Role of the Z-DNA Binding Domain in Innate Immunity and Stress Granules

“…ADAR1 has been implicated as a master regulator of the innate immunity, largely through its A-to-I editing activity to avoid unwarranted deleterious effects ( 71 – 73 ). ADAR1 knockout studies showcased the vital regulatory role of ADAR1 p150 in antiviral immune homeostasis and autoimmunity, through MDA5-MAVS sensing pathway ( 74 ), NF-κB gene regulation pathway ( 75 ) and PKR-mediated apoptosis ( 76 ) ( Figure 2 ). Editing on ubiquitous self RNA such as Alu transcripts prevents recognition by cytosolic dsRNA sensor MDA5 and erroneous autoimmune response ( 77 , 78 ).…”

Oxidative insults disrupt OPA1-mediated mitochondrial dynamics in cultured mammalian cells

“…Oxidative stressors such as H 2 O 2 cause apoptosis via activation of apoptosis-inducing factor (AIF) and caspase-3 [1,2], resulting in decreased cell viability [3]. H 2 O 2 also engages inflammatory signaling, activating the inflammasome via induction of NLRP3 and subsequent secretion of proinflammatory cytokines including IL-1B [4,5]. As such, oxidatively induced inflammation and apoptosis is a key mechanism in the pathogenesis of prevalent diseases including diabetes and cardiovascular disease [6].…”

<p>Epac1 inhibits PKR to reduce NLRP3 inflammasome proteins in retinal endothelial cells</p>

“…While little has been published on PKR in the retina or in diabetic retinopathy, a recent review suggested that PKR has a fundamental role in chronic low-grade inflammation occurring in metabolic disorders, leading to the formation of metainflammation 16. Others have reported that inhibition of PKR protects cardiomyocytes against palmitic acid-induced injury26 or hydrogen peroxide-induced apoptosis 27. Work in osteoblasts suggested that PKR induces expression of NLRP3, leading to periodontal disease 28.…”