title: Protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway plays a major role in reactive oxygen species (ROS)-mediated endoplasmic reticulum stress-induced apoptosis in diabetic cardiomyopathy.
abstract: BACKGROUND
  Endoplasmic reticulum (ER) stress is considered one of the mechanisms contributing to reactive oxygen species (ROS)-mediated cell apoptosis. In diabetic cardiomyopathy (DCM), cell apoptosis is generally accepted as the etiological factor and closely related to cardiac ROS generation. ER stress is proposed the link between ROS and cell apoptosis; however, the signaling pathways and their roles in participating ER stress-induced apoptosis in DCM are still unclear.
  
  
  METHODS
  In this study, we investigated the signaling transductions in ROS-dependent ER stress-induced cardiomocyte apoptosis in animal model of DCM. Moreover, in order to clarify the roles of IRE1 (inositol-requiring enzyme-1), PERK (protein kinase RNA (PKR)-like ER kinase) and ATF6 (activating transcription factor-6) in conducting apoptotic signal in ROS- dependent ER stress-induced cardiomocyte apoptosis, we further investigated apoptosis in high-glucose incubated cardiomyocytes with IRE1, ATF6 and PERK-knocked down respectively.
  
  
  RESULTS
  we demonstrated that the ER stress sensors, referred as PERK, IRE1 and ATF6, were activated in ROS-mediated ER stress-induced cell apoptosis in rat model of DCM which was characterized by cardiac pump and electrical dysfunctions. The deletion of PERK in myocytes exhibited stronger protective effect against apoptosis induced by high-glucose incubation than deletion of ATF6 or IRE in the same myocytes. By subcellular fractionation, rather than ATF6 and IRE1, in primary cardiomyocytes, PERK was found a component of MAMs (mitochondria-associated endoplasmic reticulum membranes) which was the functional and physical contact site between ER and mitochondria.
  
  
  CONCLUSIONS
  ROS-stimulated activation of PERK signaling pathway takes the major responsibility rather than IRE1 or ATF6 signaling pathways in ROS-medicated ER stress-induced myocyte apoptosis in DCM.
authors.forename: Zhong-Wei
authors.initials: ZW
authors.lastname: Liu
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Zhu
authors.forename: Kun-Lun
authors.initials: KL
authors.lastname: Chen
authors.forename: Xin
authors.initials: X
authors.lastname: Dong
authors.forename: Jin
authors.initials: J
authors.lastname: Wei
authors.forename: Chuan
authors.initials: C
authors.lastname: Qiu
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi, China. jiahong_xue@yeah.net.
authors.forename: Jia-Hong
authors.initials: JH
authors.lastname: Xue
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D051702:Activating Transcription Factor 6 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D058065:Diabetic Cardiomyopathies / Q000378:metabolism*; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D016166:Free Radical Scavengers / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D005947:Glucose / Q000378:metabolism; D008565:Membrane Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019892:eIF-2 Kinase / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000111:Acetylcysteine; D051702:Activating Transcription Factor 6; D016166:Free Radical Scavengers; D005947:Glucose; D008565:Membrane Proteins; D017346:Protein Serine-Threonine Kinases; D017382:Reactive Oxygen Species; D019892:eIF-2 Kinase; C497113:Atf6 protein, rat; C486557:Ern2 protein, rat