Department of Geriatrics, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China.
Department of Cardiology, The Third the People's Hospital of Bengbu, Bengbu, China.
ESC Heart Fail. 2023 Oct;10(5):3038-3045. doi: 10.1002/ehf2.14493. Epub 2023 Aug 10.
Cardiomyocyte apoptosis is an important factor leading to the occurrence and development of heart failure (HF), which is associated with high mortality of patients with cardiovascular diseases. This study aims to investigate the underlying mechanisms of HF in terms of expression and regulation patterns using bioinformatics and experimental validation.
Two HF datasets were collected: a dataset GSE112056 downloaded from the GEO database (including mRNA and miRNA sequencing data) and another is the laboratory-owned mRNA dataset. Differential mRNAs and miRNAs in the two datasets were screened using the raw Bayesian approach method. Gene Ontology was used to perform functional enrichment analysis of the differential mRNAs and co-expression network analysis of the differential mRNAs, combined with nuclear transcription factors in the differential miRNAs and mRNAs for target gene prediction. A HF cell model was constructed using mouse cardiomyocytes (HL-1), and the role and mechanism of miRNA-103-3p-Hlf (hepatic leukaemia factor) in the process of HF was verified by cell transfection, luciferase reporter gene, WB, and qPCR. We found that Hlf gene expression was decreased in the HF model group and strongly correlated with FYCO1 (FYVE and coiled-coil domain-containing protein 1) gene, a phenomenon enriched in apoptotic autophagy-related pathways. MiR-103-3p expression was up-regulated in the HF model group, and its targeting correlation with Hlf was confirmed by luciferase activity assay. In the HL-1 cell model, miR-103-3p significantly promoted apoptosis and inhibited autophagy in HL-1 cells (all P < 0.05), and overexpression of the Hlf gene reversed this phenomenon, inhibiting apoptosis and promoting autophagy in HL-1 cells (all P < 0.05).
MiR-103-3p affects myocardial cells apoptosis and autophagy by targeting Hlf, playing as a potential therapeutic biomarker for HF progression.
心肌细胞凋亡是导致心力衰竭（HF）发生和发展的重要因素，与心血管疾病患者的高死亡率相关。本研究旨在通过生物信息学和实验验证，从表达和调控模式的角度研究 HF 的潜在机制。
收集了两个 HF 数据集：一个数据集 GSE112056 从 GEO 数据库下载（包括 mRNA 和 miRNA 测序数据），另一个是实验室自有 mRNA 数据集。使用原始贝叶斯方法筛选两个数据集的差异 mRNA 和 miRNA。对差异 mRNA 进行基因本体论功能富集分析，对差异 mRNA 进行共表达网络分析，结合差异 miRNA 和 mRNA 中的核转录因子进行靶基因预测。使用小鼠心肌细胞（HL-1）构建 HF 细胞模型，通过细胞转染、荧光素酶报告基因、WB 和 qPCR 验证 miRNA-103-3p-Hlf（肝白血病因子）在 HF 过程中的作用和机制。我们发现，在 HF 模型组中 Hlf 基因表达降低，与 FYCO1（FYVE 和卷曲螺旋结构域蛋白 1）基因强烈相关，这一现象在凋亡自噬相关途径中富集。miR-103-3p 在 HF 模型组中表达上调，通过荧光素酶活性测定证实其与 Hlf 的靶向相关性。在 HL-1 细胞模型中，miR-103-3p 显著促进 HL-1 细胞凋亡，抑制自噬（均 P<0.05），而过表达 Hlf 基因则逆转了这一现象，抑制 HL-1 细胞凋亡，促进自噬（均 P<0.05）。
miR-103-3p 通过靶向 Hlf 影响心肌细胞凋亡和自噬，可能成为 HF 进展的潜在治疗生物标志物。
