Liu Langsha, Luo Fanyan
Department of Emergency, The Third Xiangya Hospital of Central South University, Changsha, China.
Department of Cardiac Surgery, Xiangya Hospital, Central South University, Changsha, China.
Genes Nutr. 2024 Aug 19;19(1):16. doi: 10.1186/s12263-024-00753-6.
Cardiac fibrosis is an important contributor to atrial fibrillation (AF). Our aim was to identify biomarkers for AF using bioinformatics methods and explore the regulatory mechanism of miR-450a-2-3p in cardiac fibrosis in mice.
Two datasets, GSE115574 and GSE79768, were obtained from the Gene Expression Omnibus (GEO) database and subsequently merged for further analysis. Differential gene expression analysis was performed to identify differentially expressed genes (DEGs) and miR-450a-2-3p-related differentially expressed genes (MRDEGs). To investigate the underlying mechanism of cardiac fibrosis, a mouse model was established by treating mice with isoproterenol (ISO) and the miR-450a-2-3p agomir.
A total of 127 DEGs and 31 MRDEGs were identified and subjected to Gene Ontology (GO) functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis to determine the functions and pathways involved in AF. In the animal model, histological analysis using HE and Masson staining, as well as quantification of the collagen volume fraction (CVF), was performed. The increased expression of α-smooth muscle actin (α-SMA), collagen type I (COL1), collagen type III (COL3), and extracellular signal-regulated kinase 1/2 (ERK(1/2)) at both the transcriptional and translational levels indicated the significant development of myocardial fibrosis in mice induced with isoproterenol (ISO). In addition, the cross-sectional area of cardiomyocytes and the expression of atrial natriuretic peptide (NPPA) and brain natriuretic peptide (NPPB) were increased in the ISO group compared with the control group. However, after overexpression of the miR-450a-2-3p agomir through caudal vein injection, there was a notable improvement in cardiac morphology in the treated group. The expression levels of α-SMA, COL1, COL3, ERK(1/2), NPPA, and NPPB were also significantly decreased.
Our study reveals the mechanistic connection between ISO-induced myocardial fibrosis and the miR-450a-2-3p/ERK(1/2) signaling pathway, highlighting its role in the development of cardiac fibrosis. Modulating miR-450a-2-3p expression and inhibiting ERK(1/2) activation are promising approaches for therapeutic intervention in patients with AF.
心脏纤维化是心房颤动（AF）的重要促成因素。我们的目的是使用生物信息学方法鉴定AF的生物标志物，并探讨miR-450a-2-3p在小鼠心脏纤维化中的调控机制。
从基因表达综合数据库（GEO）获得两个数据集GSE115574和GSE79768，随后合并以进行进一步分析。进行差异基因表达分析以鉴定差异表达基因（DEG）和miR-450a-2-3p相关差异表达基因（MRDEG）。为了研究心脏纤维化的潜在机制，通过用异丙肾上腺素（ISO）和miR-450a-2-3p激动剂处理小鼠建立小鼠模型。
共鉴定出127个DEG和31个MRDEG，并进行基因本体论（GO）功能富集分析和京都基因与基因组百科全书（KEGG）通路富集分析，以确定参与AF的功能和通路。在动物模型中，使用苏木精-伊红（HE）和Masson染色进行组织学分析，并对胶原体积分数（CVF）进行定量。α-平滑肌肌动蛋白（α-SMA）、I型胶原（COL1）、III型胶原（COL3）和细胞外信号调节激酶1/2（ERK(1/2)）在转录和翻译水平的表达增加表明，用异丙肾上腺素（ISO）诱导的小鼠心肌纤维化有显著发展。此外，与对照组相比，ISO组心肌细胞的横截面积以及心房钠尿肽（NPPA）和脑钠尿肽（NPPB）的表达增加。然而，通过尾静脉注射过表达miR-450a-2-3p激动剂后，治疗组的心脏形态有明显改善。α-SMA、COL1、COL3、ERK(1/2)、NPPA和NPPB的表达水平也显著降低。
我们的研究揭示了ISO诱导的心肌纤维化与miR-450a-2-3p/ERK(1/2)信号通路之间的机制联系，突出了其在心脏纤维化发展中的作用。调节miR-450a-2-3p表达并抑制ERK(1/2)激活是对AF患者进行治疗干预的有前景的方法。
