title: Protective effect of geranylgeranylacetone via enhancement of HSPB8 induction in desmin-related cardiomyopathy.
abstract: BACKGROUND
  An arg120gly (R120G) missense mutation in HSPB5 (alpha-beta-crystallin ), which belongs to the small heat shock protein (HSP) family, causes desmin-related cardiomyopathy (DRM), a muscle disease that is characterized by the formation of inclusion bodies, which can contain pre-amyloid oligomer intermediates (amyloid oligomer). While we have shown that small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the development of DRM is still uncertain.
  
  
  RESULTS
  In order to extend the previous in vitro findings to in vivo, we used geranylgeranylacetone (GGA), a potent HSP inducer. Oral administration of GGA resulted not only in up-regulation of the expression level of HSPB8 and HSPB1 in the heart of HSPB5 R120G transgenic (R120G TG) mice, but also reduced amyloid oligomer levels and aggregates. Furthermore, R120G TG mice treated with GGA exhibited decreased heart size and less interstitial fibrosis, as well as improved cardiac function and survival compared to untreated R120G TG mice. To address possible mechanism(s) for these beneficial effects, cardiac-specific transgenic mice expressing HSPB8 were generated. Overexpression of HSPB8 led to a reduction in amyloid oligomer and aggregate formation, resulting in improved cardiac function and survival. Treatment with GGA as well as the overexpression of HSPB8 also inhibited cytochrome c release from mitochondria, activation of caspase-3 and TUNEL-positive cardiomyocyte death in the R120G TG mice.
  
  
  CONCLUSIONS
  Expression of small HSPs such as HSPB8 and HSPB1 by GGA may be a new therapeutic strategy for patients with DRM.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan. asanbe@nch.go.jp
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Takuya
authors.initials: T
authors.lastname: Daicho
authors.forename: Reiko
authors.initials: R
authors.lastname: Mizutani
authors.forename: Toshiya
authors.initials: T
authors.lastname: Endo
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyauchi
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Kouichi
authors.initials: K
authors.lastname: Tanonaka
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D009202:Cardiomyopathies / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D003893:Desmin / Q000378:metabolism; D004224:Diterpenes / Q000494:pharmacology*; D050886:HSP20 Heat-Shock Proteins / Q000096:biosynthesis* / Q000235:genetics*; D006360:Heat-Shock Proteins / Q000096:biosynthesis / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018832:Molecular Chaperones; D009124:Muscle Proteins / Q000096:biosynthesis* / Q000235:genetics*; D020125:Mutation, Missense; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000682:Amyloid; D003893:Desmin; D004224:Diterpenes; D050886:HSP20 Heat-Shock Proteins; D006360:Heat-Shock Proteins; C486113:Hsbp1 protein, mouse; C490206:Hspb8 protein, mouse; D018832:Molecular Chaperones; D009124:Muscle Proteins; D009363:Neoplasm Proteins; D045304:Cytochromes c; C505409:Casp3 protein, mouse; D053148:Caspase 3; C031049:geranylgeranylacetone