title: Ibutilide treatment protects against ER stress induced apoptosis by regulating calumenin expression in tunicamycin treated cardiomyocytes.
abstract: BACKGROUND
  Ibutilide, a class III antiarrhythmic agent has been shown to be cardioprotective in treating atrial fibrillation, promoting cardioconversion and recently this agent has been shown to protect against ER stress induced apoptosis in cardiomyocytes. In this study we begin to identify the mechanism by which ibutilide exerts its cardioprotection in tunicamycin treated cardiomyocytes. We examined ER stress markers including calumenin; a calcium binding ER chaperone protein that has recently been linked to ER stress in cardiomyocytes, in our treated cells.
  
  
  METHODS
  To assess the effect of ibutilide we used the well characterized in vitro model of ER stress induced apoptosis in rat neonatal cardiomyocytes (RNC). RNC were treated with tunicamycin and the degree of ER stress was assessed by quantifying mRNA and protein levels of GRP78, GRP94 and calumenin, and examined the extent of apoptosis by assessing the protein levels of caspase-3/9/12, CHOP, ATF6, p-PERK, spliced XBP-1, the ratio of Bax/Bcl-2 and the percentage of deoxynucleotidyl-transferase- mediated dUTP nick end labeling (TUNEL) positive cells.
  
  
  RESULTS
  We demonstrate ibutilide attenuated the up-regulation of ER stress markers GRP78 and GRP94 and rescued the decline in calumenin mRNA and protein levels in tunicamycin treated cardiomyocytes. The up-regulation of apoptotic markers caspase-3, CHOP, ATF6, p-PERK, spliced XBP-1, the ratio of Bax/Bcl-2 and the percentage of TUNEL positive cells were also attenuated after ibutilide treatment while the protein levels of Caspase-9 and Caspase-12 were unaffected.
  
  
  CONCLUSIONS
  This study suggests another cardioprotective effect of the antiarrhythmic agent ibutilide whereby pretreatment leads to the attenuation of ER stress induced apoptosis by regulating calumenin expression. This study provides further evidence for the role of calumenin in the cardiomyocyte ER stress response.
authors.affiliation: Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, P.R. China.|Inner Mongolia Provincial Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, P.R. China.|Inner Mongolia Provincial Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Liying
authors.initials: L
authors.lastname: Xuan
authors.affiliation: First Clinical Medical College of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Cui
authors.affiliation: First Clinical Medical College of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: First Clinical Medical College of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Shaoqing
authors.initials: S
authors.lastname: Chen
authors.affiliation: Medicinal Chemistry and Pharmacology Institute, Inner Mongolia University for the Nationalities, Tongliao, Inner Mongolia, P.R. China.|Inner Mongolia Provincial Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Chengxi
authors.initials: C
authors.lastname: Wei
authors.affiliation: Inner Mongolia Provincial Key Laboratory of Mongolian Medicine Pharmacology for Cardio-Cerebral Vascular System, Tongliao, Inner Mongolia, P.R. China.|First Clinical Medical College of Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia, P.R. China.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020011:Protective Agents / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D014415:Tunicamycin / Q000633:toxicity
chemical_list: D000889:Anti-Arrhythmia Agents; D002135:Calcium-Binding Proteins; C532544:Calu protein, rat; D020011:Protective Agents; D012333:RNA, Messenger; D013449:Sulfonamides; D014415:Tunicamycin; C067192:ibutilide