title: C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation.
abstract: OBJECTIVE
  To investigate whether and how the endoplasmic reticulum (ER) stress-induced, CCAAT/enhancer-binding protein-homologous protein (CHOP)-mediated pathway regulates myocardial ischemia/reperfusion injury.
  
  
  RESULTS
  Wild-type and chop-deficient mice underwent 50 minutes of left coronary artery occlusion followed by reperfusion. Expression of chop and spliced x-box binding protein-1 (sxbp1) mRNA was rapidly and significantly increased in reperfused myocardium of wild-type mice. chop-deficient mice exhibited markedly reduced injury size after reperfusion compared with wild-type mice, accompanied by a decreasing number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cardiomyocytes. Interestingly, myocardial inflammation, as assessed by expression of inflammatory cytokines and chemokines and numbers of infiltrated inflammatory cells, was also attenuated in chop-deficient mice. Moreover, expression of interleukin-6 mRNA in response to lipopolysaccharide was enhanced by simultaneous stimulation with thapsigargin, a potent ER stressor, in wild-type cardiomyocytes but not in chop-deficient cardiomyocytes. Finally, we found that superoxide was produced in reperfused myocardium and that intravenous administration of edaravone, a free radical scavenger, immediately before reperfusion significantly suppressed the superoxide overproduction and subsequent expression of sxbp1 and chop mRNA, followed by reduced injury size in wild-type mice.
  
  
  CONCLUSIONS
  The ER stress-induced, CHOP-mediated pathway, which is activated in part by superoxide overproduction after reperfusion, exacerbates myocardial ischemia/reperfusion injury by inducing cardiomyocyte apoptosis and myocardial inflammation.
authors.affiliation: Department of Molecular Genetics, Graduate School of Medical Sciences, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miyazaki
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaikita
authors.forename: Motoyoshi
authors.initials: M
authors.lastname: Endo
authors.forename: Eiji
authors.initials: E
authors.lastname: Horio
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Miura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Tsujita
authors.forename: Seiji
authors.initials: S
authors.lastname: Hokimoto
authors.forename: Megumi
authors.initials: M
authors.lastname: Yamamuro
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.forename: Tomomi
authors.initials: T
authors.lastname: Gotoh
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Oike
mesh_terms: D000818:Animals; D000983:Antipyrine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D000077553:Edaravone; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D005786:Gene Expression Regulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012326:RNA Splicing; D012333:RNA, Messenger / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D013312:Stress, Physiological; D013481:Superoxides / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000172:deficiency* / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D018925:Chemokines; D016207:Cytokines; D004268:DNA-Binding Proteins; C497250:Ddit3 protein, mouse; D016166:Free Radical Scavengers; D018836:Inflammation Mediators; D012333:RNA, Messenger; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D013481:Superoxides; D051742:Transcription Factor CHOP; D019284:Thapsigargin; D000077553:Edaravone; D000983:Antipyrine