Protective Effect of Geranylgeranylacetone via Enhancement of HSPB8 Induction in Desmin-Related Cardiomyopathy 英文参考文献.docVIP

ProtectiveEffectofGeranylgeranylacetonevia EnhancementofHSPB8InductioninDesmin-Related Cardiomyopathy AtsushiSanbe1*,TakuyaDaicho2,ReikoMizutani1,ToshiyaEndo1,NorikoMiyauchi1,JunjiYamauchi1, KouichiTanonaka2,CharlesGlabe3,AkitoTanoue1 1Department of Pharmacology, National Research Institute for Child Health and Development, Tokyo, Japan, 2Department of Pharmacology, Tokyo University of PharmacyandLifeScience,Tokyo,Japan,3DepartmentofMolecularBiologyandBiochemistry,UniversityofCaliforniaIrvine,Irvine,California,UnitedStatesofAmerica Abstract Background: Anarg120gly (R120G) missensemutationin HSPB5 (a-b-crystallin ), which belongs tothesmall heatshock protein(HSP)family,causesdesmin-relatedcardiomyopathy(DRM),amusclediseasethatischaracterizedbytheformation ofinclusionbodies,whichcancontainpre-amyloidoligomerintermediates(amyloidoligomer).Whilewehaveshownthat small HSPs can directly interrupt amyloid oligomer formation, the in vivo protective effects of the small HSPs on the developmentofDRMisstilluncertain. Methodology/Principal Findings: In order to extend the previous in vitro findings to in vivo, we used geranylger- anylacetone(GGA),apotentHSPinducer.OraladministrationofGGAresultednotonlyinup-regulationoftheexpression levelofHSPB8andHSPB1intheheartofHSPB5R120Gtransgenic(R120GTG)mice,butalsoreducedamyloidoligomer levelsandaggregates.Furthermore,R120GTGmicetreatedwithGGAexhibiteddecreasedheartsizeandlessinterstitial 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. OverexpressionofHSPB8ledtoareductioninamyloidoligomerandaggregateformation,resultinginimprovedcardiac functionandsurvival.TreatmentwithGGAaswellastheoverexpressionofHSPB8alsoinhibitedcytochromecreleasefrom mitochondria,activationofcaspase-3andTUNEL-positivecardiomyocytedeathintheR120GTGmice. Conclusions/Significance:Expressionof