| Cardiac dysfunction in the R6/2 mouse model of Huntington's disease. | |
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MedLine Citation:
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PMID: 17126554 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Recent evidence suggests that mutant huntingtin protein-induced energetic perturbations contribute to neuronal dysfunction in Huntington's disease (HD). Given the ubiquitous expression of huntingtin, other cell types with high energetic burden may be at risk for HD-related dysfunction. Early-onset cardiovascular disease is the second leading cause of death in HD patients; a direct role for mutant huntingtin in this phenomenon remains unevaluated. Here we tested the hypothesis that expression of mutant huntingtin is sufficient to induce cardiac dysfunction, using a well-described transgenic model of HD (line R6/2). R6/2 mice developed cardiac dysfunction by 8 weeks of age, progressing to severe failure at 12 weeks, assessed by echocardiography. Limited evidence of cardiac remodeling (e.g. hypertrophy, fibrosis, apoptosis, beta(1) adrenergic receptor downregulation) was observed. Immunogold electron microscopy demonstrated significant elevations in nuclear and mitochondrial polyglutamine presence in the R6/2 myocyte. Significant alterations in mitochondrial ultrastructure were seen, consistent with metabolic stress. Increased cardiac lysine acetylation and protein nitration were observed and were each significantly associated with impairments in cardiac performance. These data demonstrate that mutant huntingtin expression has potent cardiotoxic effects; cardiac failure may be a significant complication of this important experimental model of HD. Investigation of the potential cardiotropic effects of mutant huntingtin in humans may be warranted. |
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Authors:
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Michael J Mihm; Deborah M Amann; Brandon L Schanbacher; Ruth A Altschuld; John Anthony Bauer; Kari R Hoyt |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2006-11-27 |
Journal Detail:
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Title: Neurobiology of disease Volume: 25 ISSN: 0969-9961 ISO Abbreviation: Neurobiol. Dis. Publication Date: 2007 Feb |
Date Detail:
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Created Date: 2007-01-26 Completed Date: 2007-04-11 Revised Date: 2013-06-07 |
Medline Journal Info:
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Nlm Unique ID: 9500169 Medline TA: Neurobiol Dis Country: United States |
Other Details:
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Languages: eng Pagination: 297-308 Citation Subset: IM |
Affiliation:
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Center for Cardiovascular Medicine, Columbus Children's Research Institute, 700 Children's Drive, Columbus, OH 43205, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Acetylation Animals Cardiac Output, Low / genetics, metabolism, physiopathology Cardiomegaly / genetics, metabolism, physiopathology Disease Models, Animal Down-Regulation / physiology Energy Metabolism / genetics* Heart Diseases / genetics*, metabolism, physiopathology Humans Huntington Disease / complications*, metabolism, physiopathology Male Mice Mice, Transgenic Mitochondria / genetics, metabolism, pathology Mutation / genetics Myocardium / metabolism*, pathology Nerve Tissue Proteins / genetics* Nitro Compounds / metabolism Nuclear Proteins / genetics* Peptides / metabolism Receptors, Adrenergic, beta-1 / metabolism |
| Grant Support | |
ID/Acronym/Agency:
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HL59791/HL/NHLBI NIH HHS; HL63067/HL/NHLBI NIH HHS; NS41003/NS/NINDS NIH HHS; R01 HL059791-06/HL/NHLBI NIH HHS; R01 HL063067-05/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/HTT protein, human; 0/Nerve Tissue Proteins; 0/Nitro Compounds; 0/Nuclear Proteins; 0/Peptides; 0/Receptors, Adrenergic, beta-1; 26700-71-0/polyglutamine |
| Comments/Corrections | |
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