2. Academic Validation
  3. Integration of transcriptomics, metabolomics, and lipidomics reveals the mechanisms of doxorubicin-induced inflammatory responses and myocardial dysfunction in mice

Integration of transcriptomics, metabolomics, and lipidomics reveals the mechanisms of doxorubicin-induced inflammatory responses and myocardial dysfunction in mice

  • Biomed Pharmacother. 2023 Apr 21;162:114733. doi: 10.1016/j.biopha.2023.114733.
Xin Tan 1,  Rongyi Zhang 2,  Meide Lan 1,  Cong Wen 1,  Hao Wang 1,  Junsong Guo 1,  Xuemei Zhao 1,  Hui Xu 1,  Ping Deng 3,  Huifeng Pi 3,  Zhengping Yu 3,  Rongchuan Yue 4,  Houxiang Hu 5
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 Department of Occupational Health, Third Military Medical University, Chongqing 400038, China.
  • 4 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. Electronic address: yyc@nsmc.edu.cn.
  • 5 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; Jinan University, No. 601 Huangpu Avenue West, Guangzhou 510632, China. Electronic address: hhxiang17@163.com.
PMID: 37087977 DOI: 10.1016/j.biopha.2023.114733
Abstract

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.

Keywords

Cardiotoxicity; Doxorubicin; Inflammation; Lipidomics; Metabolome; Transcriptome.

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