阿霉素致肺损伤小鼠心脏毒性的代谢组学研究

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

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。

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 chromatographymass 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 branchedchain 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.