title: Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure.
abstract: BACKGROUND
  To determine whether soluble preamyloid oligomers (PAOs) are toxic when expressed internally in the cardiomyocyte, we tested the hypothesis that cardiomyocyte-restricted expression and accumulation of a known PAO is cytotoxic and sufficient to cause heart failure.
  
  
  RESULTS
  Intracellular PAOs, the entities believed to cause toxicity in many neurodegenerative diseases, have been observed in cardiomyocytes derived from mouse and human heart failure samples. Long (>50) polyglutamine (PQ) repeats form PAOs and cause neurotoxicity in Huntington disease and other neurodegenerative diseases, whereas shorter PQ peptides are benign. We created transgenic mice in which cardiomyocyte-autonomous expression of an 83 residue-long PQ repeat (PQ83) or a non-amyloid-forming peptide of 19 PQ repeats (PQ19) as a nonpathological control was expressed. A PQ83 line with relatively low levels of expression was generated, along with a PQ19 line that expressed approximately 9-fold the levels observed in the PQ83 line. Hearts expressing PQ83 exhibited reduced cardiac function and dilation by 5 months, and all mice died by 8 months, whereas PQ19 mice had normal cardiac function, morphology, and life span. PQ83 protein accumulated within aggresomes with PAO-specific staining. The PQ83 hearts showed increased autophagosomal and lysosomal content but also showed markers of necrotic death, including inflammatory cell infiltration and increased sarcolemmal permeability.
  
  
  CONCLUSIONS
  The data confirm the hypothesis that expression of an exogenous PAO-forming peptide is toxic to cardiomyocytes and is sufficient to cause cardiomyocyte loss and heart failure in a murine model.
authors.affiliation: Department of Pediatrics, Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: J Scott
authors.initials: JS
authors.lastname: Pattison
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Alina
authors.initials: A
authors.lastname: Maloyan
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Raisa
authors.initials: R
authors.lastname: Klevitsky
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000682:Amyloid / Q000235:genetics* / Q000633:toxicity; D000686:Amyloidosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology; D000818:Animals; D017209:Apoptosis; D004452:Echocardiography; D015870:Gene Expression; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000209:etiology* / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology; D009336:Necrosis; D010455:Peptides / Q000235:genetics* / Q000633:toxicity; D012995:Solubility
chemical_list: D000682:Amyloid; D010455:Peptides; C097188:polyglutamine