Tan Xin, Zhang Rongyi, Lan Meide, Wen Cong, Wang Hao, Guo Junsong, Zhao Xuemei, Xu Hui, Deng Ping, Pi Huifeng, Yu Zhengping, Yue Rongchuan, Hu Houxiang
Department of Cardiology, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China; Academician Workstation, Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
Department of Cardiology, Nanchong Central Hospital, The Second Clinical Institute of North Sichuan Medical College, Nanchong China; Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China.
Biomed Pharmacother. 2023 Jun;162:114733. doi: 10.1016/j.biopha.2023.114733. Epub 2023 Apr 21.
Doxorubicin (DOX) is an anthracycline antineoplastic agent that has limited clinical utility due to its dose-dependent cardiotoxicity. Although the exact mechanism remains unknown, inflammatory responses have been implicated in DOX-induced cardiotoxicity (DIC). In this study, we analyzed the transcriptomic, metabolomic as well as lipidomic changes in the DOX-treated mice to explore the underlying mechanisms of DIC. We found that continuous intraperitoneal DOX injections (3 mg/kg/d) for a period of five days significantly induced cardiac dysfunction and cardiac injury in male C57BL/6 J mice (8 weeks old). This corresponded to a significant increase in the myocardial levels of IL-4, IL-6, IL-10, IL-17 and IL-12p70. Furthermore, inflammation-related genes such as Ptgs2, Il1b, Cxcl5, Cxcl1, Cxcl2, Mmp3, Ccl2, Ccl12, Nfkbia, Fos, Mapk11 and Tnf were differentially expressed in the DOX-treated group, and enriched in the IL-17 and TNF signaling pathways. Besides, amino acids, peptides, imidazoles, toluenes, hybrid peptides, fatty acids and lipids such as Hex1Cer, Cer, SM, PG and ACCa were significantly associated with the expression pattern of inflammation-related genes. In conclusion, the integration of transcriptomic, metabolomic and lipidomic data identified potential new targets and biomarkers of DIC.
多柔比星（DOX）是一种蒽环类抗肿瘤药物，因其剂量依赖性心脏毒性而临床应用受限。尽管确切机制尚不清楚，但炎症反应被认为与多柔比星诱导的心脏毒性（DIC）有关。在本研究中，我们分析了多柔比星处理的小鼠的转录组学、代谢组学以及脂质组学变化，以探索DIC的潜在机制。我们发现，对8周龄雄性C57BL/6 J小鼠连续5天腹腔注射多柔比星（3 mg/kg/d）可显著诱导心脏功能障碍和心脏损伤。这与心肌中IL-4、IL-6、IL-10、IL-17和IL-12p70水平的显著升高相对应。此外，炎症相关基因如Ptgs2、Il1b、Cxcl5、Cxcl1、Cxcl2、Mmp3、Ccl2、Ccl12、Nfkbia、Fos、Mapk11和Tnf在多柔比星处理组中差异表达，并富集于IL-17和TNF信号通路。此外，氨基酸、肽、咪唑、甲苯、杂合肽、脂肪酸和脂质如Hex1Cer、Cer、SM、PG和ACCa与炎症相关基因的表达模式显著相关。总之，转录组学、代谢组学和脂质组学数据的整合确定了DIC潜在的新靶点和生物标志物。
