Dysfunction of the CNS-heart axis in mouse models of Huntington's disease.
Dysfunction of the CNS-heart axis in mouse models of Huntington's disease.
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DOI：
10.1371/journal.pgen.1004550
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发表时间：
2014-08
期刊：
影响因子：
4.5
通讯作者：
Bates GP
中科院分区：
文献类型：
--
作者：
Mielcarek M;Inuabasi L;Bondulich MK;Muller T;Osborne GF;Franklin SA;Smith DL;Neueder A;Rosinski J;Rattray I;Protti A;Bates GP
心脏重构和收缩功能障碍发生在急性和慢性疾病过程中，包括不溶性错误折叠淀粉样蛋白聚集物的积累，这是阿尔茨海默病、帕金森病和亨廷顿病（HD）的典型特征。虽然HD主要被描述为一种神经系统疾病，但多项流行病学研究表明，HD患者心血管事件发生率高，导致心力衰竭，这是第二大死亡原因。鉴于亨廷顿蛋白普遍表达，心肌细胞可能存在hd相关功能障碍的风险。在小鼠中，在心脏特异性启动子的控制下，被迫表达扩增的polyQ重复序列导致严重的心力衰竭，随后导致寿命缩短。然而，在临床和临床前HD环境中导致心功能障碍的机制尚不清楚。为了揭示这一机制，我们采用了R6/2转基因和HdhQ150敲入HD小鼠模型。我们发现，症状前的动物出现了连接蛋白43的重新定位，肥厚标记物和Bdnf转录物的显著失调。在有症状的动物中，心脏MRI显示明显的功能改变，显示收缩功能障碍，这可能是扩张型心肌病（DCM）的一部分。这伴随着胎儿基因的重新表达，心肌细胞凋亡和中度间质纤维化。令我们惊讶的是，我们既不能在心脏组织中发现突变的HTT聚集物，也不能发现hd特异性的转录失调，即使是在疾病的最后阶段。我们假设hd相关的心肌病是由中枢自主神经通路改变引起的，尽管突变HTT在心脏中的内在作用的致病作用也可能是一个促成因素。亨廷顿氏病（HD）是一种神经退行性疾病，其突变导致超长的谷氨酰胺束，导致亨廷顿蛋白聚集。它的特点是神经系统症状和脑病理，与核和细胞质聚集和转录失调有关。尽管HD主要被认为是一种神经系统疾病，但多项流行病学研究表明，HD患者出现心血管事件导致心力衰竭的比例很高。为了揭示HD模型心功能障碍的原因，我们采用了广泛的分子和生理学方法，使用了两种建立良好的HD遗传小鼠模型。我们发现，出现症状前的动物出现了异常的间隙连接通道表达和肥厚标记物的显著失调，这可能使它们容易发生心律失常和心功能的整体改变。在有症状的动物中，这些变化伴随着胎儿基因的重新表达、心肌细胞凋亡和中度间质纤维化。令人惊讶的是，我们既不能确定心脏组织中突变的HTT聚集，也不能确定hd特异性的转录失调。因此，我们认为hd相关的心肌病可能是由中枢自主神经通路改变引起的。
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. Huntington's disease (HD) is a 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 dysregulation. 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 cause of cardiac dysfunction in HD models, we employed a wide range of molecular and physiological methods using two well established genetic mouse models of this disease. We found that pre-symptomatic animals developed aberrant gap junction channel expression and a significant deregulation of hypertrophic markers that may predispose them to arrhythmia and an overall change in cardiac function. These changes were accompanied by the re-expression of foetal genes, apoptotic cardiomyocyte loss and a moderate degree of interstitial fibrosis in the symptomatic animals. Surprisingly, we could identify neither mutant HTT aggregates in cardiac tissue nor a HD-specific transcriptional dysregulation. Therefore, we conclude that the HD-related cardiomyopathy could be driven by altered central autonomic pathways.
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影响因子：
3
作者：
Langfelder P;Horvath S
通讯作者：
Horvath S
DOI：
10.1159/000339528
发表时间：
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期刊：
Neuro-degenerative diseases
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