Cardiac dysfunction in the R6/2 mouse model of Huntington's disease

NEUROBIOLOGY OF DISEASE

卷:25

Article

Mihm, Michael J. ; Amann, Deborah M. ; Schanbacher, Brandon L. ; Altschuld, Ruth A. ; Bauer, John Anthony ; Hoyt, Karl R.

关键词: huntingtin;    Huntington's disease;    heart;    mitochondria;    polyglutamine;    cardiovascular;    transgenic;    nitrotyrosine;    acetylation;   

DOI  :  10.1016/j.nbd.2006.09.016

来源: Elsevier

【 摘 要 】

Recent evidence suggests that mutant huntingfin 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, 01 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. (c) 2006 Elsevier Inc. All rights reserved.

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