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 journalArticle

94 Citations (Scopus)

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. 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
JournalCirculation
Volume117
Issue number21
DOIs
StatePublished - May 2008
Externally publishedYes

Fingerprint

Cardiac Myocytes
Heart Failure
Poisons
Neurodegenerative Diseases
Peptides
Huntington Disease
Transgenic Mice
polyglutamine
Dilatation
Permeability
Staining and Labeling
Proteins

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. / Pattison, J. Scott; Sanbe, Atsushi; Maloyan, Alina; Osinska, Hanna; Klevitsky, Raisa; Robbins, Jeffrey.

In: Circulation, Vol. 117, No. 21, 05.2008, p. 2743-2751.

Research output: Contribution to journalArticle

Pattison, JS, Sanbe, A, Maloyan, A, Osinska, H, Klevitsky, R & Robbins, J 2008, 'Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure', Circulation, vol. 117, no. 21, pp. 2743-2751. https://doi.org/10.1161/CIRCULATIONAHA.107.750232
Pattison, J. Scott ; Sanbe, Atsushi ; Maloyan, Alina ; Osinska, Hanna ; Klevitsky, Raisa ; Robbins, Jeffrey. / Cardiomyocyte expression of a polyglutamine preamyloid oligomer causes heart failure. In: Circulation. 2008 ; Vol. 117, No. 21. pp. 2743-2751.
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AU - Robbins, Jeffrey

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AB - 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.

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