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Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease

Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been...

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Autores principales: Mielcarek, Michal, Inuabasi, Linda, Bondulich, Marie K., Muller, Thomas, Osborne, Georgina F., Franklin, Sophie A., Smith, Donna L., Neueder, Andreas, Rosinski, Jim, Rattray, Ivan, Protti, Andrea, Bates, Gillian P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125112/
https://www.ncbi.nlm.nih.gov/pubmed/25101683
http://dx.doi.org/10.1371/journal.pgen.1004550
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author Mielcarek, Michal
Inuabasi, Linda
Bondulich, Marie K.
Muller, Thomas
Osborne, Georgina F.
Franklin, Sophie A.
Smith, Donna L.
Neueder, Andreas
Rosinski, Jim
Rattray, Ivan
Protti, Andrea
Bates, Gillian P.
author_facet Mielcarek, Michal
Inuabasi, Linda
Bondulich, Marie K.
Muller, Thomas
Osborne, Georgina F.
Franklin, Sophie A.
Smith, Donna L.
Neueder, Andreas
Rosinski, Jim
Rattray, Ivan
Protti, Andrea
Bates, Gillian P.
author_sort Mielcarek, Michal
collection PubMed
description Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor.
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spelling pubmed-41251122014-08-12 Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease Mielcarek, Michal Inuabasi, Linda Bondulich, Marie K. Muller, Thomas Osborne, Georgina F. Franklin, Sophie A. Smith, Donna L. Neueder, Andreas Rosinski, Jim Rattray, Ivan Protti, Andrea Bates, Gillian P. PLoS Genet Research Article Cardiac remodelling and contractile dysfunction occur during both acute and chronic disease processes including the accumulation of insoluble aggregates of misfolded amyloid proteins that are typical features of Alzheimer's, Parkinson's and Huntington's disease (HD). While HD has been described mainly as a neurological disease, multiple epidemiological studies have shown that HD patients exhibit a high incidence of cardiovascular events leading to heart failure, and that this is the second highest cause of death. Given that huntingtin is ubiquitously expressed, cardiomyocytes may be at risk of an HD-related dysfunction. In mice, the forced expression of an expanded polyQ repeat under the control of a cardiac specific promoter led to severe heart failure followed by reduced lifespan. However the mechanism leading to cardiac dysfunction in the clinical and pre-clinical HD settings remains unknown. To unravel this mechanism, we employed the R6/2 transgenic and HdhQ150 knock-in mouse models of HD. We found that pre-symptomatic animals developed connexin-43 relocation and a significant deregulation of hypertrophic markers and Bdnf transcripts. In the symptomatic animals, pronounced functional changes were visualised by cardiac MRI revealing a contractile dysfunction, which might be a part of dilatated cardiomyopathy (DCM). This was accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis. To our surprise, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation, even at the end stage of disease. We postulate that the HD-related cardiomyopathy is caused by altered central autonomic pathways although the pathogenic effects of mutant HTT acting intrinsically in the heart may also be a contributing factor. Public Library of Science 2014-08-07 /pmc/articles/PMC4125112/ /pubmed/25101683 http://dx.doi.org/10.1371/journal.pgen.1004550 Text en © 2014 Mielcarek et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Mielcarek, Michal
Inuabasi, Linda
Bondulich, Marie K.
Muller, Thomas
Osborne, Georgina F.
Franklin, Sophie A.
Smith, Donna L.
Neueder, Andreas
Rosinski, Jim
Rattray, Ivan
Protti, Andrea
Bates, Gillian P.
Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease
title Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease
title_full Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease
title_fullStr Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease
title_full_unstemmed Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease
title_short Dysfunction of the CNS-Heart Axis in Mouse Models of Huntington's Disease
title_sort dysfunction of the cns-heart axis in mouse models of huntington's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4125112/
https://www.ncbi.nlm.nih.gov/pubmed/25101683
http://dx.doi.org/10.1371/journal.pgen.1004550
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