Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437100, PR China; Xianning Medical College, Hubei University of Science and Technology, Xianning 437100, PR China.
Hubei Key Laboratory of Diabetes and Angiopathy, Hubei University of Science and Technology, Xianning 437100, PR China; Department of Pharmacy, University of South China Affiliated Changsha Central Hospital, Changsha 410004, PR China.
Toxicol In Vitro. 2023 Dec;93:105662. doi: 10.1016/j.tiv.2023.105662. Epub 2023 Aug 18.
This study aimed to investigate the effect of miRNAs involving oxidative stress response in doxorubicin (DOX)-induced cardiotoxicity based on the data from Gene Expression Omnibus (GEO) database and experimental results via integrated bioinformatics analysis. MiRNA expression profiles of DOX-induced cardiotoxicity in rat myocardial tissues and adult rat cardiomyocytes (ARC) were extracted from GEO datasets (GSE36239). Differential expression miRNA (DEMs) were separately captured in rat myocardial tissues and in ARC, and intersected between rat myocardial tissues and ARC via Venny 2.1. Subsequently, Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analyzed 46 target genes of miR-143, one of 6 DEMs, and HIF-1 and PI3K-Akt signaling pathway were significantly enriched. Further experimental results showed DOX-induced oxidative stress downregulated the expression of miR-143, and then promoted target gene Bbc3 expression and H9c2 apoptosis, the intervention of phosphocreatine (PCr) or N-acetyl-L-cystine (NAC) alleviated oxidative stress, apoptosis and Bbc3 expression, upregulated miR-143 in DOX-induced cardiotoxicity in vivo and in vitro. Our findings elucidated the regulatory network between miR-143 and oxidative stress in DOX-induced cardiotoxicity, and might unveiled a potential biomarker and molecular mechanisms, which could be helpful to the diagnosis and treatment of DOX-induced cardiotoxicity.
本研究旨在基于基因表达综合数据库（GEO）数据库的数据和通过综合生物信息学分析获得的实验结果，研究涉及氧化应激反应的 miRNAs 在多柔比星（DOX）诱导的心脏毒性中的作用。从 GEO 数据集（GSE36239）中提取 DOX 诱导的大鼠心肌组织和成年大鼠心肌细胞（ARC）中的心脏毒性的 miRNA 表达谱。分别在大鼠心肌组织和 ARC 中捕获差异表达 miRNA（DEMs），并通过 Venny 2.1 在大鼠心肌组织和 ARC 之间进行交叉。随后，对 miR-143 的 46 个靶基因进行基因本体论（GO）和京都基因与基因组百科全书通路（KEGG）分析，miR-143 是 6 个 DEMs 之一，HIF-1 和 PI3K-Akt 信号通路显著富集。进一步的实验结果表明，DOX 诱导的氧化应激下调了 miR-143 的表达，进而促进了靶基因 Bbc3 的表达和 H9c2 细胞凋亡，磷酸肌酸（PCr）或 N-乙酰-L-半胱氨酸（NAC）的干预减轻了 DOX 诱导的氧化应激、凋亡和 Bbc3 的表达，上调了体内和体外 DOX 诱导的心脏毒性中的 miR-143。我们的研究结果阐明了 miR-143 与 DOX 诱导的心脏毒性中氧化应激之间的调控网络，可能揭示了一个潜在的生物标志物和分子机制，有助于 DOX 诱导的心脏毒性的诊断和治疗。
