title: 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 H2O2induced apoptosis and injury. To elucidate the mechanism, we revealed that inhibition of PKR alleviated H2O2induced apoptosis companied by decreased caspase3/7 activity, BAX and caspase-3 expression. We also revealed that inhibition of PKR suppressed H2O2induced NFκB pathway and NLRP3 activation. Finally, we found ADAR1 mRNA and protein expression were both induced after H2O2treatment 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 H2O2to limit PKR activation simultaneously. These findings identify a novel role for PKR/ADAR1 in myocardial reperfusion injury.
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Yongyi
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of endocrinology, Xi'an Central Hospital, Shaanxi, China.
authors.forename: Min
authors.initials: M
authors.lastname: Men
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Xie
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jianggui
authors.initials: J
authors.lastname: Shan
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Chengxi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Jidong
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Wengang
authors.initials: W
authors.lastname: Yang
authors.affiliation: Department of Cardiovascular Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors.forename: Song
authors.initials: S
authors.lastname: Xue
authors.affiliation: Department of Cardiovascular Surgery, Zhong Shan Hospital, School of Medicine, Fudan University, Shanghai, China.
authors.forename: Changfa
authors.initials: C
authors.lastname: Guo
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity*; D007249:Inflammation / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors*
chemical_list: D006861:Hydrogen Peroxide; C000602769:EIF2AK2 protein, human; D019892:eIF-2 Kinase