title: Mechanical unloading activates FoxO3 to trigger Bnip3-dependent cardiomyocyte atrophy.
abstract: BACKGROUND
  Mechanical assist device therapy has emerged recently as an important and rapidly expanding therapy in advanced heart failure, triggering in some patients a beneficial reverse remodeling response. However, mechanisms underlying this benefit are unclear.
  
  
  RESULTS
  In a model of mechanical unloading of the left ventricle, we observed progressive myocyte atrophy, autophagy, and robust activation of the transcription factor FoxO3, an established regulator of catabolic processes in other cell types. Evidence for FoxO3 activation was similarly detected in unloaded failing human myocardium. To determine the role of FoxO3 activation in cardiac muscle in vivo, we engineered transgenic mice harboring a cardiomyocyte-specific constitutively active FoxO3 mutant (caFoxO3(flox);αMHC-Mer-Cre-Mer). Expression of caFoxO3 triggered dramatic and progressive loss of cardiac mass, robust increases in cardiomyocyte autophagy, declines in mitochondrial biomass and function, and early mortality. Whereas increases in cardiomyocyte apoptosis were not apparent, we detected robust increases in Bnip3 (Bcl2/adenovirus E1B 19-kDa interacting protein 3), an established downstream target of FoxO3. To test the role of Bnip3, we crossed the caFoxO3(flox);αMHC-Mer-Cre-Mer mice with Bnip3-null animals. Remarkably, the atrophy and autophagy phenotypes were significantly blunted, yet the early mortality triggered by FoxO3 activation persisted. Rather, declines in cardiac performance were attenuated by proteasome inhibitors. Consistent with involvement of FoxO3-driven activation of the ubiquitin-proteasome system, we detected time-dependent activation of the atrogenes program and sarcomere protein breakdown.
  
  
  CONCLUSIONS
  In aggregate, these data point to FoxO3, a protein activated by mechanical unloading, as a master regulator that governs both the autophagy-lysosomal and ubiquitin-proteasomal pathways to orchestrate cardiac muscle atrophy.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8573, USA.
authors.forename: Dian J
authors.initials: DJ
authors.lastname: Cao
authors.forename: Nan
authors.initials: N
authors.lastname: Jiang
authors.forename: Andrew
authors.initials: A
authors.lastname: Blagg
authors.forename: Janet L
authors.initials: JL
authors.lastname: Johnstone
authors.forename: Raj
authors.initials: R
authors.lastname: Gondalia
authors.forename: Misook
authors.initials: M
authors.lastname: Oh
authors.forename: Xiang
authors.initials: X
authors.lastname: Luo
authors.forename: Kai-Chun
authors.initials: KC
authors.lastname: Yang
authors.forename: John M
authors.initials: JM
authors.lastname: Shelton
authors.forename: Beverly A
authors.initials: BA
authors.lastname: Rothermel
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Gillette
authors.forename: Gerald W
authors.initials: GW
authors.lastname: Dorn
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
mesh_terms: D000818:Animals; D001284:Atrophy; D001343:Autophagy; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006333:Heart Failure / Q000628:therapy*; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D015398:Signal Transduction; D043743:Ubiquitin-Protein Ligase Complexes / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: C508686:BNip3 protein, mouse; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D043743:Ubiquitin-Protein Ligase Complexes; D046988:Proteasome Endopeptidase Complex