title: Attenuation of CHOP-mediated myocardial apoptosis in pressure-overloaded dominant negative p38α mitogen-activated protein kinase mice.
abstract: OBJECTIVE
  Pressure overload stimulation is known to elicit disturbances in the endoplasmic reticulum (ER), which leads to ER stress (ERS). p38 mitogen-activated protein kinase (MAPK) plays an important role in mediating apoptotic processes, however, the roles of this kinase in activating ERS-initiated apoptosis in pressure-overloaded hearts are largely unknown.
  
  
  METHODS
  We clarified the role of p38α MAPK in ERS-associated apoptosis by subjecting transgenic mice displaying cardiac specific dominant negative (DN) mutant p38α MAPK over-expression to seven day pressure overload.
  
  
  RESULTS
  Seven days pressure overload resulted in the same extent of cardiac hypertrophy and ERS in the wild-type (WT) and DN p38α mice compared with the sham mice. It also activated inositol-requiring enzyme (Ire)-1α and its downstream molecule, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2 in the WT and DN p38α mice compared with the sham mice. Interestingly, increased myocardial apoptosis and the up-regulation of CCAAT/enhancer binding protein homology protein (CHOP) expression compared with those in the sham mice were found in the aortic-banded WT mice, but not in the DN p38α mice.
  
  
  CONCLUSIONS
  Partial inhibition of p38α protein blocked the activation of CHOP-mediated apoptotic processes during pressure overload by partially inhibiting signaling from the Ire-1α/TRAF2 to its down-stream molecule, CHOP.
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, Higashijima, Niigata City, Japan.
authors.forename: Flori R
authors.initials: FR
authors.lastname: Sari
authors.forename: Bambang
authors.initials: B
authors.lastname: Widyantoro
authors.forename: Rajarajan A
authors.initials: RA
authors.lastname: Thandavarayan
authors.forename: Meilei
authors.initials: M
authors.lastname: Harima
authors.forename: Arun Prasath
authors.initials: AP
authors.lastname: Lakshmanan
authors.forename: Shaosong
authors.initials: S
authors.lastname: Zhang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
authors.forename: Kenji
authors.initials: K
authors.lastname: Suzuki
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001011:Aorta / Q000293:injuries / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D015870:Gene Expression; D005799:Genes, Dominant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009929:Organ Size; D011312:Pressure / Q000009:adverse effects; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C497250:Ddit3 protein, mouse; D008565:Membrane Proteins; C499176:T2bp protein, mouse; D051742:Transcription Factor CHOP; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D048308:Mitogen-Activated Protein Kinase 14