Proteomic profiling of cardiomyopathic tissue from the aged mdx model of Duchenne muscular dystrophy reveals a drastic decrease in laminin, nidogen and annexin
Proteomic profiling of cardiomyopathic tissue from the aged mdx model of Duchenne muscular dystrophy reveals a drastic decrease in laminin, nidogen and annexin
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DOI：
10.1002/pmic.201200578
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发表时间：
2013-08-01
期刊：
影响因子：
3.4
通讯作者：
Ohlendieck, Kay
中科院分区：
文献类型：
--
作者：
Holland, Ashling;Dowling, Paul;Ohlendieck, Kay
大多数患有杜氏肌营养不良症的患者会出现心肌病并发症，因此需要对全球心脏变化进行大规模的蛋白质组学研究，以鉴定肌营养不良病的新蛋白质标志物。来自x连锁营养不良mdx小鼠的衰老心脏已被证明表现出不同的心肌病病理方面。为了确定肌营养不良蛋白缺乏的心脏中蛋白质组的年龄相关变化，用无标记LC-MS/MS检测了年轻和老年mdx小鼠的心肌病组织。67种蛋白质存在明显的年龄依赖性变化，其中28种蛋白质的丰度较低，39种蛋白质的表达水平增加。17种蛋白发生了剧烈变化，包括Ig链和转铁蛋白的增加，层粘连蛋白、氮原蛋白和膜联蛋白的急剧减少。一项针对野生型和mdx型心脏的免疫印迹调查证实了这些蛋白质组学发现，并说明了自然衰老对肌营养不良蛋白缺乏的影响。这些蛋白质组范围的改变提示心肌纤维中肌营养不良蛋白缺乏的基底层结构和细胞骨架网络的解体，退行性心脏的潜在自身免疫反应中抗体水平的增加，过量铁的代偿结合以及营养不良相关心肌病中代谢途径的普遍扰动。
The majority of patients afflicted with Duchenne muscular dystrophy develop cardiomyopathic complications, warranting large-scale proteomic studies of global cardiac changes for the identification of new protein markers of dystrophinopathy. The aged heart from the X-linked dystrophic mdx mouse has been shown to exhibit distinct pathological aspects of cardiomyopathy. In order to establish age-related alterations in the proteome of dystrophin-deficient hearts, cardiomyopathic tissue from young versus aged mdx mice was examined by label-free LC-MS/MS. Significant age-dependent alterations were established for 67 proteins, of which 28 proteins were shown to exhibit a lower abundance and 39 proteins were found to be increased in their expression levels. Drastic changes were demonstrated for 17 proteins, including increases in Ig chains and transferrin, and drastic decreases in laminin, nidogen and annexin. An immunblotting survey of young and old wild-type versus mdx hearts confirmed these proteomic findings and illustrated the effects of natural aging versus dystrophin deficiency. These proteome-wide alterations suggest a disintegration of the basal lamina structure and cytoskeletal network in dystrophin-deficient cardiac fibres, increased levels of antibodies in a potential autoimmune reaction of the degenerating heart, compensatory binding of excess iron and a general perturbation of metabolic pathways in dystrophy-associated cardiomyopathy.