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阿霉素致肺损伤小鼠心脏毒性的代谢组学研究

吴婧, 于心悦, 徐燕, 黄寅, 张语馨

吴婧, 于心悦, 徐燕, 黄寅, 张语馨. 阿霉素致肺损伤小鼠心脏毒性的代谢组学研究[J]. 中国药科大学学报, 2023, 54(2): 198-207. DOI: 10.11665/j.issn.1000-5048.20221218001
引用本文: 吴婧, 于心悦, 徐燕, 黄寅, 张语馨. 阿霉素致肺损伤小鼠心脏毒性的代谢组学研究[J]. 中国药科大学学报, 2023, 54(2): 198-207. DOI: 10.11665/j.issn.1000-5048.20221218001
WU Jing, YU Xinyue, XU Yan, HUANG Yin, ZHANG Yuxin. Metabolomics profiling of doxorubicin-induced cardiotoxicity in mice with lung injury[J]. Journal of China Pharmaceutical University, 2023, 54(2): 198-207. DOI: 10.11665/j.issn.1000-5048.20221218001
Citation: WU Jing, YU Xinyue, XU Yan, HUANG Yin, ZHANG Yuxin. Metabolomics profiling of doxorubicin-induced cardiotoxicity in mice with lung injury[J]. Journal of China Pharmaceutical University, 2023, 54(2): 198-207. DOI: 10.11665/j.issn.1000-5048.20221218001

阿霉素致肺损伤小鼠心脏毒性的代谢组学研究

基金项目: 江苏省基础研究计划自然科学基金资助项目(No.BK20220193)

Metabolomics profiling of doxorubicin-induced cardiotoxicity in mice with lung injury

Funds: This study was supported by the Basic Research Program (Natural Science Foundation) of Jiangsu Province (No.BK20220193)
  • 摘要: 化疗药物诱导的心脏毒性近年来广受关注,但有关肺损伤状态下化疗对心脏代谢的影响尚未见报道。本研究采用博莱霉素(BLM)和阿霉素(DOX)构建肺损伤叠加心肌损伤小鼠模型:C57BL/6J小鼠随机分为4组,分别为对照组(CON)、BLM组(单次气管滴注5.0 mg/kg BLM)、DOX组(腹腔注射7.5 mg/kg DOX,每周1次,连续两周)和DOX+BLM组,以血清标志物和组织病理学检查评价心脏损伤程度。采用气质联用(GC-MS)和液质联用(LC-MS)技术对心脏样本进行非靶向代谢组学分析。结果表明,与CON组相比,单独给予BLM可导致小鼠肺损伤,但对心脏代谢轮廓无显著影响;单独给予DOX心脏代谢轮廓发生显著变化,主要差异代谢物为氨基酸、脂肪酸、磷脂等;联合给予BLM和DOX后心脏代谢稳态被严重扰乱,尤其是支链氨基酸蓄积更加严重。研究证实,在肺损伤状态下DOX可导致心脏代谢轮廓发生更显著的变化,并初步聚焦支链氨基酸代谢通路。研究结果为进一步深入探讨化疗药物心脏毒性机制提供了参考。
    Abstract: Cardiotoxicity of cancer chemotherapeutics has received considerable attention in recent years.However, the effects of chemotherapy on cardiometabolic perturbation with lung injury have rarely been reported. Thus, we constructed a mouse model of myocardial injury superimposed on lung injury with a combination of bleomycin (BLM) and doxorubicin (DOX).C57BL/6J mice were randomly divided into four groups: control group (CON), BLM group (intratracheal infusion with single doses of 5 mg/kg), DOX group (intraperitoneal injection of 7.5 mg/kg/week, two weeks) and DOX+BLM group. The cardiac injury of mice was evaluated by serum biochemical parameters and histopathology.Cardiometabolic perturbation was investigated using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS).The results showed that, compared with the CON group, BLM alone caused lung injury yet with no significant effects on the cardiometabolic profile; DOX alone had significant perturbations in the cardiometabolic profile, and the main differential metabolites were amino acids, fatty acids, phospholipids, etc.; the combination of BLM and DOX caused more severe disturbance of cardiometabolic homeostasis in mice, especially accumulation of branched-chain amino acids.This study confirmed that DOX can lead to more significant changes in the cardiometabolic profile in the presence of lung injury, with an initial focus on the branched-chain amino acid metabolic pathway.This research provides scientific data for in-depth study of the cardiotoxicity mechanism of chemotherapeutic agents.
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出版历程
  • 收稿日期:  2022-12-17
  • 修回日期:  2023-02-27
  • 刊出日期:  2023-04-24

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