title: Desmin modifications associate with amyloid-like oligomers deposition in heart failure.
abstract: OBJECTIVE
  The ultimate cause of heart failure (HF) is not known to date. The cytoskeletal protein desmin is differentially modified and forms amyloid-like oligomers in HF. We postulated that desmin post-translational modifications (PTMs) could drive aberrant desmin aggregation in HF. Therefore, we identified these PTMs and investigated their impact on desmin amyloidogenicity in human and experimental HF.
  
  
  RESULTS
  We detected increased levels of selectively phosphorylated and cleaved desmin in a canine pacing model of dyssynchronous HF (DHF) compared with either controls or animals treated with cardiac resynchronization therapy (CRT). This unique animal model combines clinically relevant features with the possibility of a partly rescued phenotype. We confirmed analogous changes in desmin modifications in human HF and identified two phosphorylation sites within a glycogen synthase kinase 3 (GSK3) consensus sequence. Desmin-positive oligomers were also increased in DHF hearts compared with controls. Their amyloid properties were decreased by treatment with CRT or an anti-amyloid small molecule. Finally, we confirmed GSK3's involvement with desmin phosphorylation using an in vitro model.
  
  
  CONCLUSIONS
  Based on these findings, we postulate a new mechanism of cardiac toxicity based on the PTM-driven accumulation of desmin amyloid-like oligomers. Phosphorylation and cleavage as well as oligomers formation are reduced by treatment (CRT) indicating a relationship between the three. Finally, the decrease of desmin amyloid-like oligomers with CRT or small molecules points both to a general mechanism of HF based on desmin toxicity that is independent of protein mutations and to novel potential therapies.
authors.affiliation: Department of Medicine, Division of Cardiology, Johns Hopkins University, Baltimore, MD 21224, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Agnetti
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Halperin
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kirk
authors.forename: Khalid
authors.initials: K
authors.lastname: Chakir
authors.forename: Yurong
authors.initials: Y
authors.lastname: Guo
authors.forename: Linda
authors.initials: L
authors.lastname: Lund
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicolini
authors.forename: Tiziano
authors.initials: T
authors.lastname: Gherli
authors.forename: Carlo
authors.initials: C
authors.lastname: Guarnieri
authors.forename: Claudio M
authors.initials: CM
authors.lastname: Caldarera
authors.forename: Gordon F
authors.initials: GF
authors.lastname: Tomaselli
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Van Eyk
mesh_terms: D000818:Animals; D058406:Cardiac Resynchronization Therapy; D003893:Desmin / Q000378:metabolism*; D004285:Dogs; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000502:physiology; D066329:Protein Aggregates; D011499:Protein Processing, Post-Translational / Q000502:physiology; D040901:Proteomics / Q000379:methods
chemical_list: D003893:Desmin; D066329:Protein Aggregates; D038362:Glycogen Synthase Kinase 3
keywords: Amyloid; Desmin; Heart failure; Post-translational modifications; Proteomics