title: Ablation of C/EBP homologous protein attenuates endoplasmic reticulum-mediated apoptosis and cardiac dysfunction induced by pressure overload.
abstract: BACKGROUND
  Apoptosis may contribute to the development of heart failure, but the role of apoptotic signaling initiated by the endoplasmic reticulum in this condition has not been well clarified.
  
  
  RESULTS
  In myocardial samples from patients with heart failure, quantitative real-time polymerase chain reaction revealed an increase in messenger RNA for C/EBP homologous protein (CHOP), a transcriptional factor that mediates endoplasmic reticulum-initiated apoptotic cell death. We performed transverse aortic constriction or sham operation on wild-type (WT) and CHOP-deficient mice. The CHOP-deficient mice showed less cardiac hypertrophy, fibrosis, and cardiac dysfunction compared with WT mice at 4 weeks after transverse aortic constriction, although the contractility of isolated cardiomyocytes from CHOP-deficient mice was not significantly different from that in the WT mice. In the hearts of CHOP-deficient mice, phosphorylation of eukaryotic translation initiation factor 2alpha, which may reduce protein translation, was enhanced compared with WT mice. In the hearts of WT mice, CHOP-increased apoptotic cell death with activation of caspase-3 was observed at 4 weeks after transverse aortic constriction. In contrast, CHOP-deficient mice had less apoptotic cell death and lower caspase-3 activation at 4 weeks after transverse aortic constriction. Furthermore, the Bcl2/Bax ratio was decreased in WT mice, whereas this change was significantly blunted in CHOP-deficient mice. Real-time polymerase chain reaction microarray analysis revealed that CHOP could regulate several Bcl2 family members in failing hearts.
  
  
  CONCLUSIONS
  We propose the novel concept that CHOP, which may modify protein translation and mediate endoplasmic reticulum-initiated apoptotic cell death, contributes to development of cardiac hypertrophy and failure induced by pressure overload.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, Japan. minamino@cardiology.med.osaka-u.ac.jp
authors.forename: Hai Ying
authors.initials: HY
authors.lastname: Fu
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Tadashi
authors.initials: T
authors.lastname: Isomura
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Asai
authors.forename: Tamaki
authors.initials: T
authors.lastname: Sawada
authors.forename: Keiji
authors.initials: K
authors.lastname: Okuda
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Asano
authors.forename: Shoji
authors.initials: S
authors.lastname: Sanada
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Masanori
authors.initials: M
authors.lastname: Asakura
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000172:deficiency / Q000235:genetics*; D009202:Cardiomyopathies / Q000473:pathology / Q000601:surgery; D017931:DNA Primers; D006333:Heart Failure / Q000235:genetics*; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013318:Stroke Volume
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D017931:DNA Primers; D012333:RNA, Messenger