Insight into the underlying molecular mechanism of dilated cardiomyopathy through integrative analysis of data mining, iTRAQ-PRM proteomics and bioinformatics

DCM is a common cardiomyopathy worldwide, which is characterized by ventricular dilatation and systolic dysfunction. DCM is one of the most common diseases contributing to sudden death and heart failure. However, our understanding of its molecular mechanisms is limited because of its etiology and underlying mechanisms. Poor access to human myocardium is a significant limitation in the study of DCM. Firstly, DCM disease target genes were downloaded from public databases, and 935 genes were identified as key target genes. Next, a total of 787 DEPs, including 353 up-regulated and 434 down-regulated proteins, were identified in our animal experiment. The functional annotation of these DEPs revealed complicated molecular mechanisms including oxidation-reduction process, tricarboxylic acid cycle, protein folding, and triggered a series of molecular pathways involving TCA cycle, Oxidative phosphorylation, Cardiac muscle contraction. Finally, the DEPs were analyzed for association with the target genes screened in the public dataset. The overlapping proteins were validated by parallel reaction monitoring (PRM). We obtained 154 key proteins and further determined the importance of these three pathways. Together, this study provided deep insights into the detailed molecular mechanisms of DCM and facilitated the identification of potential proteins associated with it.

扩张型心肌病（Dilated Cardiomyopathy, DCM）是全球范围内常见的心肌病，以心室扩张与收缩功能障碍为典型特征，亦是引发心源性猝死与心力衰竭的常见病因之一。然而，由于其病因及潜在发病机制复杂，目前学界对其分子层面的致病机制认知仍较为有限，而人类心肌组织获取难度大，更是扩张型心肌病研究面临的重大限制因素。
首先，本研究从公共数据库中下载扩张型心肌病的疾病靶基因，最终筛选得到935个核心靶基因。其次，通过动物实验共鉴定出787个差异表达蛋白（Differentially Expressed Proteins, DEPs），其中上调蛋白353个、下调蛋白434个。对上述DEPs进行功能注释后，揭示了其涉及的复杂分子机制，包括氧化还原过程、三羧酸循环、蛋白质折叠等，并激活了涵盖三羧酸循环、氧化磷酸化及心肌收缩的一系列分子通路。
最后，本研究对DEPs与公共数据集筛选得到的靶基因开展关联分析，通过平行反应监测（Parallel Reaction Monitoring, PRM）技术对其中的重叠蛋白进行验证，最终得到154个核心蛋白，并进一步明确了上述三条通路在疾病中的关键作用。
综上，本研究深入解析了扩张型心肌病的具体分子机制，同时为该病潜在关联蛋白的筛选提供了重要依据。