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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.
Insights
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.
Abstract:
Huntington's disease (HD) is neurodegenerative disorder for which the mutation results in an extra-long tract of glutamines that causes the huntingtin protein to aggregate. It is characterized by neurological symptoms and brain pathology that is associated with nuclear and cytoplasmic aggregates and with transcriptional deregulation. Despite the fact that HD has been recognized principally as a neurological disease, there are multiple epidemiological studies showing that HD patients exhibit a high rate of cardiovascular events leading to heart failure. To unravel the mechanistic basis of cardiac dysfunction in HD, we employed a wide range of molecular techniques using the well-established genetic R6/2 mouse model that develop a considerable degree of the cardiac atrophy at end stage disease. We found that chronic treatment with isoproterenol, a potent beta-adrenoreceptor agonist, did not change the overall gross morphology of the HD murine hearts. However, there was a partial response to the beta-adrenergenic stimulation by the further re-expression of foetal genes. In addition we have profiled the expression level of Hdacs in the R6/2 murine hearts and found that the isoproterenol stimulation of Hdac expression was partially blocked. For the first time we established the Hdac transcriptional profile under hypertrophic conditions and found 10 out of 18 Hdacs to be markedly deregulated. Therefore, we conclude that R6/2 murine hearts are not able to respond to the chronic isoproterenol treatment to the same degree as wild type hearts and some of the hypertrophic signals are likely attenuated in the symptomatic HD animals.
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