Manipulation of death pathways in desmin-related cardiomyopathy.

Abstract

RATIONALE:

Transgenic mice with cardiac specific overexpression of mutated alphaB-crystallin (CryAB(R120G)) display Desmin-related myopathy (DRM) with dilated cardiomyopathy and heart failure. Our previous studies showed the presence of progressive mitochondrial abnormalities and activation of apoptotic cell death in CryAB(R120G) transgenic hearts. However, the role of mitochondrial dysfunction and apoptosis in the overall course of the disease was unclear.

OBJECTIVE:

We tested the hypothesis that prevention of apoptosis would ameliorate CryAB(R120G) pathology and decrease morbidity.

METHODS AND RESULTS:

We crossed CryAB(R120G) mice to transgenic mice with cardiac specific overexpression of Bcl-2. Sustained Bcl-2 overexpression in CryAB(R120G) hearts prolonged CryAB(R120G) transgenic mice survival by 20%. This was associated with decreased mitochondrial abnormalities, restoration of cardiac function, prevention of cardiac hypertrophy, and attenuation of apoptosis. CryAB(R120G) misfolded protein aggregation was significantly reduced in the double transgenic. However, inhibition of apoptotic signaling resulted in the upregulation of autophagy and alternative death pathways, the net result being increased necrosis.

CONCLUSION:

Although Bcl-2 overexpression prolonged life in this DRM model, in the absence of apoptosis, another death pathway was activated.

• Authors: Alina Maloyan, Jennifer Sayegh, Hanna Osinska, Balvin H L Chua, Jeffrey Robbins
• Journal: Circulation research (Circ Res) Vol. 106 Issue 9 Pg. 1524-32 (May 14 2010) ISSN: 1524-4571 [Electronic] United States
• PMID: 20360253 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Desmin
• Proto-Oncogene Proteins c-bcl-2
• alpha-Crystallin B Chain

Topics

• 3T3 Cells
• Animals
• Apoptosis
• Cardiomyopathy, Hypertrophic (metabolism, pathology)
• Cells, Cultured
• Desmin (metabolism)
• Disease Models, Animal
• Fibroblasts (metabolism)
• Mice
• Mice, Transgenic
• Mitochondria (metabolism)
• Mutation
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Signal Transduction
• Survival Rate
• alpha-Crystallin B Chain (genetics, metabolism)