基于血浆和心肌内小分子的代谢组学方法评价心肌缺血大鼠模型  

Evaluation of myocardial ischemia rat model based on metabonomic method of small molecule metabolites of plasma and cardiac muscle

作　　者：严蓓[1,2] 阿基业[1] 郝海平[1] 王广基[1] 刘林生[1] 查伟斌[1] 张颖[1] 顾胜华[1] 

机构地区：[1]中国药科大学药物代谢动力学重点实验室,江苏南京210009 [2]卫生部北京医院药学部临床药理室,北京100730

出　　处：《药学学报》2013年第1期104-112,共9页Acta Pharmaceutica Sinica

基　　金：国家重大基础"973"研究项目(2011CB505303);国家自然科学基金资助项目(81202601);中国药科大学天然药物活性组分与药效国家重点实验室项目(2011AJY)

摘　　要：异丙肾上腺素(ISO)诱导的心肌缺血动物模型广泛用于心肌缺血研究和药效评价。内源性化合物的代谢谱可以提供ISO诱导的心肌缺血大鼠体内生化代谢信息。本研究采用连续10天大鼠皮下注射ISO(2 mg.kg 1)的方法造模。心肌病理切片和血浆肌酸激酶检测显示造模成功(心肌缺血形成)。利用GC-TOF/MS检测大鼠血浆和心肌的内源性代谢物,利用模式识别进行数据处理。结果显示ISO诱导的模型大鼠血浆的代谢谱与正常大鼠明显不同,停止注射后10天内大鼠血浆代谢谱有自行恢复的趋势;另发现造模10天大鼠心肌和正常大鼠心肌也可明显区分。模型大鼠血浆和心肌中的潜在生物标志物既有共性,又各具特点。生化代谢通路分析提示心肌缺血涉及能量代谢、糖代谢、脂代谢、核苷酸代谢和氨基酸代谢异常,并与氧化应激密切相关。提示代谢组学可以检测体内多种代谢/循环状态,是评价ISO诱导的心肌缺血模型大鼠体内代谢变化的有效工具,为进一步在分子水平进行综合药效评价奠定了基础。Isoproterenol（ISO）-induced myocardial ischemia animal model has been widely applied to the study of myocardial ischemia and evaluation of drug efficacy.Metabolic profiling of endogenous compounds can make a deep insight into biochemical process of the ISO-induced myocardial ischemia rats.Herein,rats were treated with ISO（2 mg.kg 1） for 10 days.After the model was established by measuring myocardial histopathology and plasma creatine kinase,GC/TOF-MS was used to determine endogenous metabolites in plasma and cardiac muscle of rats,and pattern recognition was used to process the data.Results showed that the plasma metabolic profiling of ISO-induced myocardial ischemia rats was significantly different from that of the control,and it had the tendency to the normal state after the discontinue of ISO injection.Besides,the cardiac muscle of rats treated with ISO for 10 days and the normal cardiac muscle could also be separated clearly.The potential biomarkers in plasma and cardiac muscle of model rats had homogeneity and their own specialty.Biochemical metabolic pathway analysis indicated that this myocardial ischemia model was involved in the alternation of energy metabolism,saccharometabolism,lipid metabolism,nucleoside metabolism and amino acid metabolism,and in relationship with oxidative stress.These findings revealed that metabonomics may be a promising tool to evaluate myocardial ischemia rat model induced by ISO and could further extend the study of pharmacodynamic action of drugs at the molecular level.

关 键 词：代谢组学 血浆 心肌 心肌缺血大鼠模型 异丙肾上腺素 

分 类 号：R917[医药卫生—药物分析学]