基于代谢组学研究糖尿病状态下阿司匹林治疗中血小板高反应的发生机制

doi:10.12092/j.issn.1009-2501.2020.03.002

中国临床药理学与治疗学 ›› 2020, Vol. 25 ›› Issue (3): 246-256.doi: 10.12092/j.issn.1009-2501.2020.03.002

基于代谢组学研究糖尿病状态下阿司匹林治疗中血小板高反应的发生机制

张浩文1，朱业锦2，武相3，陈寒昱4，宋玉磊1，卞尧尧1，郝海平2，陈晓虎3

¹南京中医药大学，南京 210023，江苏；²中国药科大学药物代谢动力学重点实验室，南京 210009，江苏;³江苏省中医院，南京 210029，江苏；⁴南京特殊教育师范学院康复科学学院，南京 210038，江苏

收稿日期:2019-06-05 修回日期:2020-02-22 出版日期:2020-03-26 发布日期:2020-04-13
通讯作者: 陈晓虎，男，博士，教授，博士生导师，研究方向：心血管疾病。
作者简介:张浩文，男，博士，讲师，研究方向：心血管疾病。 Tel：025-85811722 E-mail: zhwdoctor@njucm.edu.cn
基金资助:
国家自然科学基金资助项目（81573908）；江苏省自然科学基金资助项目（BK20180827）；南京中医药大学“江苏高校护理学优势学科建设工程资助项目”（2019YSHL060）

Study on high on-aspirin platelet reactivity in diabetic mice based on metabonomics

ZHANG Haowen¹, ZHU Yejin², WU Xiang³, CHEN Hanyu⁴, SONG Yulei ¹, BIAN Yaoyao ¹, HAO Haiping ², CHEN Xiaohu³

¹ Nanjing University of Chinese Medicine, Nanjing 210023, Jiangsu, China; ²Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, Jiangsu, China; ³Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, Jiangsu, China; ⁴School of Rehabilitation Science, Nanjing Normal University of Special Education, Nanjing 210038, Jiangsu, China

Received:2019-06-05 Revised:2020-02-22 Online:2020-03-26 Published:2020-04-13

摘要/Abstract

摘要： 目的:利用代谢组学技术，从内源性物质的代谢变化角度探讨糖尿病状态下阿司匹林治疗中血小板高反应（HAPR）的发生机制。方法:本研究采用高脂饲料联合链脲佐菌素建立2型糖尿病（T2DM）小鼠模型，随后将小鼠按体质量随机分为正常组、T2DM组、正常+阿司匹林组、T2DM+阿司匹林组。通过气相色谱-飞行时间质谱（GC-TOF/MS）检测不同组别小鼠血浆内源性代谢物，利用多变量统计方法对数据进行分析。结果:长期给予阿司匹林的T2DM雌性小鼠的血小板表面CD62P及血浆血栓素（TXB2）/6-keto-PGF1α的比值与模型组相比无显著改变，这表明在T2DM雌性小鼠上，阿司匹林药效降低，发生HAPR；正常组和正常+阿司匹林组之间代谢组别的趋离程度明显大于T2DM和T2DM+阿司匹林组，进一步证实T2DM雌性小鼠发生了HAPR；生化代谢通路分析提示T2DM小鼠HAPR的发生与糖酵解或糖异生作用、丙酮酸代谢、柠檬酸循环、抗坏血酸代谢、花生四烯酸等代谢通路的增强密切相关。结论:代谢组检测中筛选所获得的差异代谢物提示了糖尿病状态下HAPR的发生涉及不同代谢途径的改变，这为进一步阐明糖尿病状态下HAPR的生物学机制奠定了物质基础。

关键词: 代谢组学, 糖尿病, 阿司匹林治疗中血小板高反应

Abstract: AIM: To explore the underlying mechanism of aspirin-related high on-aspirin platelet reactivity (HAPR) in diabetic state from the perspective of endogenous metabolic changes in metabolomics. METHODS:Type 2 diabetes mellitus (T2DM) mice model was established by the combination treatment of high-fat diet and streptozotocin injections. Mice were randomly divided into Normal group, T2DM group, Normal+aspirin group and T2DM+aspirin group. GC/TOF-MS was used to determine the plasmatic endogenous metabolites of mice. The data were analyzed applying multivariate statistical method. RESULTS:The expression of platelet CD62P and ratio of TXB2/6-keto-PGF1α in the plasma of female T2DM mice showed no significant difference compared with that of the model group. The degree of divergence between normal and normal+aspirin groups was significantly greater than that between T2DM and T2DM+aspirin groups. Biochemical metabolic pathway analysis revealed that HAPR in diabetic mice was linked to glycolysis, gluconeogenesis, pyruvate metabolism, citric acid cycle, ascorbic acid metabolism, and arachidonic acid metabolic pathways. CONCLUSION:The different metabolites obtained in metabolome assay suggests that the HAPR in diabetic state involved several different metabolic pathways, which can better elucidate the biological mechanism of diabetes-associated HAPR.

Key words: metabonomics, diabetes, high on-aspirin platelet reactivity

中图分类号:

R969
R587.1

张浩文，朱业锦，武相，陈寒昱，宋玉磊，卞尧尧，郝海平，陈晓虎. 基于代谢组学研究糖尿病状态下阿司匹林治疗中血小板高反应的发生机制[J]. 中国临床药理学与治疗学, 2020, 25(3): 246-256.

ZHANG Haowen, ZHU Yejin, WU Xiang, CHEN Hanyu, SONG Yulei, BIAN Yaoyao, HAO Haiping, CHEN Xiaohu. Study on high on-aspirin platelet reactivity in diabetic mice based on metabonomics[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2020, 25(3): 246-256.

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基于代谢组学研究糖尿病状态下阿司匹林治疗中血小板高反应的发生机制

Study on high on-aspirin platelet reactivity in diabetic mice based on metabonomics

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