敲除TSP1通过氨基酸和糖代谢通路对阿霉素所致心肌损伤的作用  

Effects of knockout TSP1 on adriamycininduced myocardial injury through amino acids and glycose metabolism pathways

作　　者：占敏 卓丰 吴敏[1] 李科浩 张守华[1] 杨豆 ZHAN Min;ZHUO Feng;WU Min;LI Ke-hao;ZHANG Shou-hua;YANG Dou(Department of General Surgery,Jiangxi Provincial Children's Hospital,Nanchang 330038,Jiangxi,China;不详)

机构地区：[1]江西省儿童医院普外科,江西南昌330038 [2]江西省儿童医院心脏病中心,江西南昌330038 [3]南昌大学药学院,江西南昌330006

出　　处：《广东医学》2023年第2期161-167,共7页Guangdong Medical Journal

基　　金：江西省卫生健康委科技计划项目(202211240、202211246)。

摘　　要：目的利用代谢组学方法阐明敲除血小板反应蛋白1(TSP1)通过调节小分子化合物的代谢,减轻阿霉素(ADM)致心肌损伤。方法以24只野生型C57BL/6小鼠和24只TSP1基因敲除(TSP1^(-/-))小鼠为实验对象,分为4组:WM组(n=12)、TSP1^(-/-)组(n=12)和WM-ADM组(n=12)、TSP1^(-/-)-ADM组(n=12)。WM组和TSP1^(-/-)组小鼠腹腔注射生理盐水,WM-ADM组和TSP1^(-/-)-ADM组小鼠腹腔注射ADM以建立慢性心功能衰竭(CHF)模型。以血清生化[肌酸激酶(creatine kinase,CK)、肌酸激酶同工酶(creatine kinase isoenzymes,CK-MB)、乳酸脱氢酶(lactate dehydrogenase,LDH)]和心脏组织苏木精-伊红(hematoxylin-eosin,HE)染色为指标评价注射ADM后小鼠心肌损伤情况,以基于核磁共振(1HNMR)的代谢组学技术来研究4组小鼠血清中小分子代谢物的变化。结果血清生化和心脏组织HE染色显示,注射ADM后TSP1^(-/-)小鼠心脏组织损伤比野生小鼠明显减轻。代谢组学研究显示,敲除TSP1后明显影响小鼠体内的氨基酸代谢。野生型小鼠注射ADM后,血清亮氨酸、异亮氨酸、缬氨酸、乳酸、丙氨酸、乙酸和丙酮酸等变化明显;TSP1^(-/-)小鼠注射ADM后上述血清代谢物水平明显回调。结论本研究发现TSP1^(-/-)小鼠可能通过调节氨基酸和糖代谢来减弱ADM造成的心肌损伤。Objective To clarify that knockout of thrombospondins-1(TSP1)can reduce myocardial injury caused by adriamycin(ADM)by regulating the metabolism of small molecular compounds.Methods In this study,24 wild C57BL/6 mice and 24 knockout of TSP1 gene(TSP1^(-/-))mice were selected and divided into 4 groups(each n=12),mice in Group WM and Group TSP1^(-/-)received normal saline intraperitoneal injection,and mice in Group WM-AMD and Group TSP1^(-/-)-AMD received ADM intraperitoneal injection.The myocardial injury of mice was evaluated by serum biochemistry for creatine kinase(CK),creatine kinase isoenzymes(CK-MB),and lactate dehydrogenase(LDH),and HE staining of cardiac tissue after ADM injection.The changes of small molecule metabolites in serum of the 4 groups of mice were studied by metabolomics technology based on nuclear magnetic resonance(1HNMR).Results Serum biochemistry and HE staining of cardiac tissue showed that the cardiac tissue injury of TSP1^(-/-)mice was significantly milder than that of wild mice after ADM injection.Metabonomics studies showed that knockout of TSP1 significantly affected amino acid metabolism in mice.The changes of serum leucine,isoleucine,valine,lactic acid,alanine,acetic acid and pyruvate were obvious in wild mice after ADM injection.The levels of serum metabolites in TSP1^(-/-)mice were significantly reduced after ADM injection.Conclusion TSP1^(-/-)mice may reduce the myocardial injury caused by ADM by regulating amino acid and glucose metabolism.

关 键 词：TSP1 阿霉素 心肌损伤 代谢组学 氨基酸代谢 

分 类 号：R542.2[医药卫生—心血管疾病] R977.6[医药卫生—内科学]