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Manipulation of death pathways in desmin-related cardiomyopathy

Alina Maloyan1, Jennifer Sayegh, Hanna Osinska

  • 1Molecular Cardiovascular Biology, Heart Institute, Cincinnati Children's Hospital, Cincinnati, Ohio, USA.

Circulation Research
|April 3, 2010
PubMed
Abstract

Insights

Preventing apoptosis in Desmin-related myopathy (DRM) mice with mutated alphaB-crystallin (CryAB(R120G)) extended survival. However, blocking apoptosis activated alternative death pathways, increasing necrosis.

Area of Science:

  • Cardiovascular Research
  • Mitochondrial Biology
  • Cell Death Pathways

Background:

  • Transgenic mice overexpressing mutated alphaB-crystallin (CryAB(R120G)) develop Desmin-related myopathy (DRM), dilated cardiomyopathy, and heart failure.
  • Previous studies indicated progressive mitochondrial dysfunction and apoptosis in CryAB(R120G) hearts, but their precise role remained unclear.

Purpose of the Study:

  • To investigate if preventing apoptosis could ameliorate CryAB(R120G) pathology and reduce disease severity.
  • To test the hypothesis that inhibiting programmed cell death would improve cardiac function and survival.

Main Methods:

  • Crossed CryAB(R120G) mice with mice overexpressing Bcl-2 (an apoptosis inhibitor) in the heart.
  • Assessed survival rates, mitochondrial function, cardiac hypertrophy, apoptosis, protein aggregation, and alternative cell death pathways.

Main Results:

  • Bcl-2 overexpression increased survival of CryAB(R120G) mice by 20%.
  • This was linked to reduced mitochondrial abnormalities, improved cardiac function, prevented hypertrophy, and less apoptosis.
  • Misfolded protein aggregation decreased, but autophagy and necrosis increased.

Conclusions:

  • While inhibiting apoptosis prolonged survival in this DRM model, it did not fully resolve the pathology.
  • Alternative cell death pathways, including necrosis, were activated when apoptosis was suppressed.

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