title: Partial inactivation of cardiac 14-3-3 protein in vivo elicits endoplasmic reticulum stress (ERS) and activates ERS-initiated apoptosis in ERS-induced mice.
abstract: OBJECTIVE
  Excessive endoplasmic reticulum stress (ERS) triggers apoptosis in various conditions including diabetic cardiomyopathy and pressure overload-induced cardiac hypertrophy and heart failure. The primary function of 14-3-3 protein is to inhibit apoptosis, but the roles of this protein in protecting against cardiac ERS and apoptosis are largely unknown.
  
  
  METHODS
  We investigated the roles of 14-3-3 protein in vivo during cardiac ERS and apoptosis induced by pressure overload or thapsigargin injection using transgenic (TG) mice that showed cardiac-specific expression of dominant negative (DN) 14-3-3eta.
  
  
  RESULTS
  Cardiac positive apoptotic cells and the expression of glucose-regulated protein (GRP)78, inositol-requiring enzyme (Ire)1alpha, tumor necrosis factor receptor (TNFR)-associated factor (TRAF)2, CCAAT/enhancer binding protein homology protein (CHOP), caspase-12, and cleaved caspase-12 protein were significantly increased in the pressure-overload induced DN 14-3-3eta mice compared with that in the WT mice. Furthermore, thapsigargin injection significantly increased the expression of GRP78 and TRAF2 expression in DN 14-3-3eta mice compared with that in the WT mice.
  
  
  CONCLUSIONS
  The enhancement of 14-3-3 protein may provide a novel protective therapy against cardiac ERS and ERS-initiated apoptosis, at least in part, through the regulation of CHOP and caspase-12 via the Ire1alpha/TRAF2 pathway.
authors.affiliation: Department of Clinical Pharmacology, Niigata University of Pharmacy and Applied Life Sciences, 265-1 Higashijima, Niigata City, Japan.
authors.forename: Flori R
authors.initials: FR
authors.lastname: Sari
authors.forename: Kenichi
authors.initials: K
authors.lastname: Watanabe
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: Shaosong
authors.initials: S
authors.lastname: Zhang
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Muslin
authors.forename: Makoto
authors.initials: M
authors.lastname: Kodama
authors.forename: Yoshifusa
authors.initials: Y
authors.lastname: Aizawa
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D006332:Cardiomegaly / Q000378:metabolism; D053454:Caspase 12 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism; D011312:Pressure; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D013312:Stress, Physiological; D047992:TNF Receptor-Associated Factor 2 / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D048948:14-3-3 Proteins; D022762:CCAAT-Enhancer-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D047992:TNF Receptor-Associated Factor 2; D019284:Thapsigargin; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D053454:Caspase 12