Document Detail


Cardiac dysfunction in the R6/2 mouse model of Huntington's disease.
MedLine Citation:
PMID:  17126554     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Michael J Mihm; Deborah M Amann; Brandon L Schanbacher; Ruth A Altschuld; John Anthony Bauer; Kari R Hoyt
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2006-11-27
Journal Detail:
Title:  Neurobiology of disease     Volume:  25     ISSN:  0969-9961     ISO Abbreviation:  Neurobiol. Dis.     Publication Date:  2007 Feb 
Date Detail:
Created Date:  2007-01-26     Completed Date:  2007-04-11     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  9500169     Medline TA:  Neurobiol Dis     Country:  United States    
Other Details:
Languages:  eng     Pagination:  297-308     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
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:
HL59791/HL/NHLBI NIH HHS; HL63067/HL/NHLBI NIH HHS; NS41003/NS/NINDS NIH HHS; R01 HL059791/HL/NHLBI NIH HHS; R01 HL063067/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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