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The Huntington's disease-related cardiomyopathy prevents a hypertrophic response in the R6/2 mouse model
Michal Mielcarek1, Marie K Bondulich1, Linda Inuabasi1
1Department of Medical and Molecular Genetics, King's College London, London, United Kingdom.
Plos One
|October 1, 2014
Summary
Huntington's disease (HD) impairs cardiac function. In R6/2 mice, isoproterenol treatment showed a blunted response, indicating attenuated hypertrophic signals in symptomatic HD hearts.
Area of Science:
- Cardiovascular Biology
- Neurodegenerative Diseases
- Molecular Genetics
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by expanded glutamine tracts in the huntingtin protein, leading to protein aggregation.
- While primarily neurological, HD is linked to increased cardiovascular events and heart failure in patients.
- The R6/2 mouse model exhibits cardiac atrophy, making it suitable for studying HD-related cardiac dysfunction.
Purpose of the Study:
- To investigate the mechanistic basis of cardiac dysfunction in Huntington's disease.
- To assess the response of HD murine hearts to beta-adrenergic stimulation.
- To characterize the transcriptional profile of histone deacetylases (Hdac) under hypertrophic conditions in HD.
Main Methods:
- Utilized the R6/2 mouse model of Huntington's disease.
- Administered chronic isoproterenol treatment to assess beta-adrenergic response.
- Employed molecular techniques to profile gene expression, including Hdac levels.
- Analyzed cardiac morphology and gene re-expression patterns.
Main Results:
- Chronic isoproterenol treatment did not alter gross cardiac morphology in R6/2 mice.
- A partial re-expression of foetal genes was observed, indicating a limited response to beta-adrenergic stimulation.
- Isoproterenol-induced Hdac expression was partially blocked in R6/2 hearts.
- Ten out of 18 profiled Hdacs were significantly deregulated under hypertrophic conditions.
Conclusions:
- R6/2 murine hearts exhibit an attenuated response to chronic isoproterenol treatment compared to wild-type hearts.
- Symptomatic HD animals show impaired hypertrophic signaling pathways.
- These findings highlight significant cardiac abnormalities in HD beyond neurological symptoms.
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