Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China.
BMC Cardiovasc Disord. 2024 Jul 10;24(1):350. doi: 10.1186/s12872-024-03967-z.
Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study.
The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes.
The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines.
This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.
多柔比星、伊达比星和表柔比星等抗肿瘤药物已被发现由于氧化应激-线粒体功能障碍-铁死亡（ORMFs）而对心脏产生不良影响，这些因素是蒽环类药物引起心脏毒性的促成因素。为了更好地理解这一现象，本研究分析了 ORMFs 基因的时间分辨测量。
使用人 3D 心脏微组织细胞模型研究三种蒽环类药物对 ORMFs 基因的影响。在两种剂量（治疗和毒性）下收集 14 天的转录组数据。WGCNA 鉴定关键模块相关基因，功能富集分析研究 ssGSEA 量化的生物学过程，如免疫细胞浸润和血管生成。从心力衰竭患者和对照受试者中采集活检。收集 GSE59672 和 GSE2965 进行验证。分子对接用于鉴定蒽环类药物与关键基因的相互作用。
在体内或体外筛选 ORMFs 基因。使用 WGCNA 将六个共表达基因模块分组，其中 MEblue 是最显著的模块。获得与蓝色模块与动态响应基因相交的八个关键基因：CD36、CDH5、CHI3L1、HBA2、HSD11B1、OGN、RPL8 和 VWF。与对照样本相比，在体外 ANT 处理设置中，除 RPL8 外，所有关键基因均下调，其表达水平随时间变化。根据功能分析，关键模块相关基因参与血管生成和免疫系统途径。在所有 ANT 处理设置中，ssGSEA 显示血管生成评分和免疫细胞活性显著下调，包括激活的 CD4 T 细胞、未成熟 B 细胞、记忆 B 细胞、自然杀伤细胞、1 型 T 辅助细胞和 2 型 T 辅助细胞。分子对接显示 RPL8 和 CHI3L1 对蒽环类药物表现出显著的结合亲和力。
本研究重点关注人心脏微组织和 ANT 治疗患者心脏活检中 ORMFs 基因的动态特征。研究表明，ORMFs 基因可能导致蒽环类药物引起的心脏毒性中的免疫浸润和血管生成。对这些基因的深入了解可能有助于改善疾病的诊断和治疗。
