Department of Ultrasound, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
Department of Cardiology, The Fourth Affiliated Hospital of China Medical University, Shenyang 110032, China.
Oxid Med Cell Longev. 2022 Mar 31;2022:1450610. doi: 10.1155/2022/1450610. eCollection 2022.
Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disease and can result in substantial disability. The current study explored the potentials of long noncoding RNA- (lncRNA-) circular RNA- (circRNA-) microRNA- (miRNA-) messenger RNA (mRNA) networks in HCM. Firstly, HCM-related microarray data were procured from the GEO database, with differentially expressed genes (DEGs) obtained. HCM-related target genes were retrieved in combination with GeneCards and CTD databases, and candidate target genes were subsequently obtained by intersection screening. Further, an interaction network diagram of candidate target genes was constructed using the STRING database, and the hub genes in the network were determined according to the core degree. The "ClusterProfiler" package of the R software was adopted for GO and KEGG analyses of candidate target genes, to analyze the potential molecular pathways in HCM. Next, upstream miRNA, lncRNA, and circRNA of ACTB were predicted with RNAInter, mirDIP, TargetScan, DIANA-LncBase, and StarBase databases, followed by construction of lncRNA/circRNA-miRNA-mRNA coexpression networks. ACTB, miR-206, circFN1, and ADAMTS9-AS1 expression in peripheral blood samples from HCM patients and normal healthy controls were detected using RT-qPCR. Moreover, rat cardiomyocyte cell lines H9c2 and HEK293 cells were selected for verification of competitive endogenous RNA (ceRNA) regulation mechanism. A total of 15 candidate target genes related to HCM were screened using the online databases. Further protein-protein interaction analysis identified ACTB as the hub gene for HCM. The targeted binding relationship between miR-206, miR-145-5p, miR-1-3p, and ACTB was found. Furthermore, ADAMTS9-AS1 and circFN1 were discovered as the upstream genes of miR-206. Moreover, ADAMTS9-AS1, circFN1, and ACTB were found to be poorly expressed, and miR-206 was highly expressed in HCM. experimentation further confirmed that ADAMTS9-AS1 and circFN1 could competitively bind to miR-206, thereby augmenting ACTB expression. Taken all, ADAMTS9-AS1/circFN1-miR-206-ACTB regulatory network may involve in HCM occurrence, providing a novel theoretical basis for in-depth understanding of mechanism of HCM.
肥厚型心肌病（HCM）是一种遗传性心脏病，可导致严重的残疾。本研究探讨了长非编码 RNA（lncRNA）-环状 RNA（circRNA）-微小 RNA（miRNA）-信使 RNA（mRNA）网络在 HCM 中的潜力。首先，从 GEO 数据库中获取 HCM 相关的微阵列数据，获得差异表达基因（DEGs）。结合 GeneCards 和 CTD 数据库检索 HCM 相关靶基因，通过交集筛选获得候选靶基因。然后，使用 STRING 数据库构建候选靶基因的互作网络图，并根据核心度确定网络中的枢纽基因。采用 R 软件的“ClusterProfiler”包对候选靶基因进行 GO 和 KEGG 分析，以分析 HCM 中的潜在分子途径。接下来，使用 RNAInter、mirDIP、TargetScan、DIANA-LncBase 和 StarBase 数据库预测 ACTB 的上游 miRNA、lncRNA 和 circRNA，构建 lncRNA/circRNA-miRNA-mRNA 共表达网络。采用 RT-qPCR 检测 HCM 患者和正常健康对照者外周血样本中 ACTB、miR-206、circFN1 和 ADAMTS9-AS1 的表达。此外，选择大鼠心肌细胞系 H9c2 和 HEK293 细胞验证竞争性内源 RNA（ceRNA）调控机制。使用在线数据库筛选出与 HCM 相关的 15 个候选靶基因。进一步的蛋白质-蛋白质相互作用分析鉴定出 ACTB 为 HCM 的枢纽基因。发现 miR-206、miR-145-5p、miR-1-3p 与 ACTB 之间存在靶向结合关系。此外，发现 ADAMTS9-AS1 和 circFN1 是 miR-206 的上游基因。此外，在 HCM 中发现 ADAMTS9-AS1、circFN1 和 ACTB 表达水平降低，而 miR-206 表达水平升高。实验进一步证实 ADAMTS9-AS1 和 circFN1 可以竞争性结合 miR-206，从而增加 ACTB 的表达。总之，ADAMTS9-AS1/circFN1-miR-206-ACTB 调控网络可能参与 HCM 的发生，为深入了解 HCM 发病机制提供了新的理论依据。
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