Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure

J. Scott Pattison, Atsushi Sanbe, Alina Maloyan, Hanna Osinska, Raisa Klevitsky, Jeffrey Robbins

Research output: Contribution to journalArticlepeer-review

110 Scopus citations


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. METHODS AND 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 ≈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.

Original languageEnglish (US)
Pages (from-to)2743-2751
Number of pages9
Issue number21
StatePublished - May 2008
Externally publishedYes


  • Amyloid
  • Cardiomyopathy
  • Cardiovascular diseases
  • Heart diseases
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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