Reversal of amyloid-induced heart disease in desmin-related cardiomyopathy

Atsushi Sanbe, Hanna Osinska, Chet Villa, James Gulick, Raisa Klevitsky, Charles G. Glabe, Rakez Kayed, Jeffrey Robbins

Research output: Contribution to journalArticlepeer-review

107 Scopus citations


Amyloid oligomers, similar to the toxic entities found in Alzheimer's disease patients and in other amyloid-based diseases, are present in cardiomyocytes derived from human heart-failure patients and in animal models of desmin-related cardiomyopathy (DRM). The R120G mutation in α-B-crystallin (CryAB) causes DRM and is characterized by aggresomes containing CryAB R120G and amyloid oligomer. In this study, we show that aggresome levels do not correlate with disease. Blocking aggresome formation results in increased levels of toxic amyloid oligomer and decreased cardiomyocyte viability. We confirmed the primary toxicity of intrasarcoplasmic amyloid accumulation in the cardiomyocytes by ectopic expression of the amyloidogenic peptide PQ81, which consists of multiple repeats of a polyglutamine tract. We then addressed the issue of disease reversibility by placing CryAB R120G under inducible cardiomyocyte-specific expression in transgenic mice. The mice developed aggresomes and contained high concentrations of amyloid oligomer in the heart, resulting in cardiac disease. Cessation of CryABR120G expression in symptomatic mice improved cardiac function and rescued all of the animals from premature death. Rescue was accompanied by significant decreases in amyloid oligomer without a significant reduction in aggresomes. Blocking cardiac amyloid oligomer formation, even after cardiac dysfunction presents, may be a therapeutic strategy in DRM as well as in other types of cardiac disease in which significant amyloid accumulation occurs.

Original languageEnglish (US)
Pages (from-to)13592-13597
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number38
StatePublished - Sep 20 2005
Externally publishedYes


  • Cardiomyocytes

ASJC Scopus subject areas

  • General


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