Department of Cardiology, Zhongnan Hospital of Wuhan University, No. 169 Donghu Road, Wuchang District, Wuhan, 430071, China.
Institute of Myocardial Injury and Repair, Wuhan University, Wuhan, China.
BMC Med Genomics. 2021 Nov 29;14(1):283. doi: 10.1186/s12920-021-01134-3.
Chronic chagasic cardiomyopathy (CCC) is the leading cause of heart failure in Latin America and often causes severe inflammation and fibrosis in the heart. Studies on myocardial function and its molecular mechanisms in patients with Chronic chagasic cardiomyopathy are very limited. In order to understand the development and progression of Chronic chagasic cardiomyopathy and find targets for its diagnosis and treatment, the field needs to better understand the exact molecular mechanisms involved in these processes.
The mRNA microarray datasets GSE84796 (human) and GSE24088 (mouse) were obtained from the Gene Expression Omnibus (GEO) database. Homologous genes between the two species were identified using the online database mining tool Biomart, followed by differential expression analysis, gene enrichment analysis and protein-protein interaction (PPI) network construction. Cytohubba plug-in of Cytoscape software was used to identify Hub gene, and miRNet was used to construct the corresponding miRNA-mRNA regulatory network. miRNA-related databases: miRDB, Targetscan and miRWalk were used to further evaluate miRNAs in the miRNA-mRNA network. Furthermore, Comparative Toxicogenomics Database (CTD) and L1000 Platform were used to identify hub gene-related drugs.
A total of 86 homologous genes were significantly differentially expressed in the two datasets, including 73 genes with high expression and 13 genes with low expression. These differentially expressed genes were mainly enriched in the terms of innate immune response, signal transduction, protein binding, Natural killer cell mediated cytotoxicity, Tuberculosis, Chemokine signaling pathway, Chagas disease and PI3K-Akt signaling pathway. The top 10 hub genes LAPTM5, LCP1, HCLS1, CORO1A, CD48, TYROBP, RAC2, ARHGDIB, FERMT3 and NCF4 were identified from the PPI network. A total of 122 miRNAs were identified to target these hub genes and 30 of them regulated two or more hub genes at the same time. miRDB, Targetscan and miRWalk were further analyzed and screened out hsa-miR-34c-5p, hsa-miR-34a-5p and hsa-miR-16-5p as miRNAs regulating these hub genes. Finally, Progesterone, Flutamide, Nimesulide, Methotrexate and Temozolomide were identified to target these hub genes and might be targeted therapies for Chronic chagasic cardiomyopathy.
In this study, the potential genes associated with Chronic chagasic cardiomyopathy are identified and a miRNA-mRNA regulatory network is constructed. This study explores the molecular mechanisms of Chronic chagasic cardiomyopathy and provides important clues for finding new therapeutic targets.
慢性恰加斯病性心肌病（CCC）是拉丁美洲心力衰竭的主要原因，常导致心脏严重炎症和纤维化。关于慢性恰加斯病患者心肌功能及其分子机制的研究非常有限。为了了解慢性恰加斯病的发展和进展，并找到其诊断和治疗的靶点，该领域需要更好地了解这些过程中涉及的确切分子机制。
从基因表达综合数据库（GEO）中获得了 mRNA 微阵列数据集 GSE84796（人类）和 GSE24088（小鼠）。使用在线数据库挖掘工具 Biomart 识别两种物种之间的同源基因，然后进行差异表达分析、基因富集分析和蛋白质-蛋白质相互作用（PPI）网络构建。使用 Cytoscape 软件的 Cytohubba 插件识别 Hub 基因，并构建相应的 miRNA-mRNA 调控网络。使用 miRNA 相关数据库：miRDB、Targetscan 和 miRWalk 进一步评估 miRNA-mRNA 网络中的 miRNA。此外，还使用比较毒理学基因组学数据库（CTD）和 L1000 平台来识别 Hub 基因相关药物。
在这两个数据集中共发现 86 个同源基因存在明显的差异表达，其中 73 个基因高表达，13 个基因低表达。这些差异表达的基因主要富集在固有免疫反应、信号转导、蛋白结合、自然杀伤细胞介导的细胞毒性、结核病、趋化因子信号通路、恰加斯病和 PI3K-Akt 信号通路等术语中。从 PPI 网络中鉴定出前 10 个 Hub 基因 LAPTM5、LCP1、HCLS1、CORO1A、CD48、TYROBP、RAC2、ARHGDIB、FERMT3 和 NCF4。总共鉴定出 122 个 miRNA 靶向这些 Hub 基因，其中 30 个 miRNA 同时调节两个或更多 Hub 基因。进一步分析和筛选出 hsa-miR-34c-5p、hsa-miR-34a-5p 和 hsa-miR-16-5p 作为调节这些 Hub 基因的 miRNA。最后，鉴定出 Progesterone、Flutamide、Nimesulide、Methotrexate 和 Temozolomide 靶向这些 Hub 基因，可能成为慢性恰加斯病性心肌病的靶向治疗药物。
本研究鉴定了与慢性恰加斯病性心肌病相关的潜在基因，并构建了 miRNA-mRNA 调控网络。本研究探讨了慢性恰加斯病性心肌病的分子机制，为寻找新的治疗靶点提供了重要线索。
