药学学报, 2019, 54(8): 1470-1475
刘嫄, 严蓓, 胡欣, 史爱欣. 肺动脉高压比格犬血清代谢组学研究及sGC003对其代谢模式的作用[J]. 药学学报, 2019, 54(8): 1470-1475.
LIU Yuan, YAN Bei, HU Xin, SHI Ai-xin. Metabolomic investigate into the serum of pulmonary hypertension Beagle dogs and the effect of sGC003[J]. Acta Pharmaceutica Sinica, 2019, 54(8): 1470-1475.

刘嫄1, 严蓓1, 胡欣2,3, 史爱欣1,3
1. 北京医院临床试验研究中心, 国家老年医学中心, 北京 100730;
2. 北京医院药学部, 北京 100730;
3. 药物临床风险与个体化应用评价北京市重点实验室, 北京 100730
基于脱氢野百合碱诱导的肺动脉高压(pulmonary hypertension,PH)比格犬模型,利用GC-TOF-MS代谢组学分析技术的方法,对比格犬PH模型组(n=11)及健康对照组(n=8)的血清进行代谢组学分析,结果显示,血清中检测出514个化合物,模式识别分析后PH模型组与健康对照组能够很好地区分开,表明两组间的血清代谢谱存在显著差异,鉴定出15种造成差异的代谢物即PH的潜在生物标志物包括:葡萄糖、果糖等糖类,1-单棕榈酸甘油、苹果酸等,氨基酸类甘氨酸、3-氰丙氨酸,其涉及的乙醛酸和二羧酸代谢、柠檬酸循环和淀粉及蔗糖代谢通路均发生了不同程度的紊乱。此外,探讨应用sGC003抗肺动脉高压化合物干预后(n=15),PH比格犬代谢特征的改变,给药组与模型组和健康对照组比较后存在差异,ANOVA统计分析结果提示,给予sGC003化合物对肺动脉高压疾病比格犬的异常代谢物具有调节作用,同时也一定程度上改变了正常机体内源性代谢物。本研究更为全面深入地理解了PH的代谢改变及创新药物sGC003化合物的调节作用,为代谢组学应用于肺动脉高压的早期诊断奠定了基础,为sGC003化合物的应用提供依据。本研究中动物实验方案获得北京日新科技有限公司实验动物管理委员会的批准。
关键词:    肺动脉高压      代谢组学      GC-TOF-MS      sGC003      内源性代谢物     
Metabolomic investigate into the serum of pulmonary hypertension Beagle dogs and the effect of sGC003
LIU Yuan1, YAN Bei1, HU Xin2,3, SHI Ai-xin1,3
1. Clinical Trial Center, Beijing Hospital, National Center of Gerontology, Beijing 100730, China;
2. Department of Pharmacy, Beijing Hospital, Beijing 100730, China;
3. Assessment of Clinical Drugs Risk and Individual Application Key Laboratory, Beijing 100730, China
Based on dehydrogenation of monocrotaline-induced Beagle dog model of pulmonary hypertension (PH), GC-TOF-MS metabolomics technique was used to identify potential biomarkers and biologically significant changes in the serum. Pattern recognition method was used for processing metabolomics data to compare PH Beagle dogs (n=11) versus healthy controls (n=8). The results show that 514 compounds were detected in the serum. The profiles of PH models and healthy controls can be distinguished clearly, indicating that there are significant differences in the metabolic profiles. Data analysis revealed 15 types of potential biomarkers, including amino acids glycine and 3-cyanoalanine, glucose, fructose, 1-monopalmitic acid glycerin, and malic acid. Diversified metabolites and their metabolic pathways have been analyzed. We found that different degrees of turbulence and disorganization occurred in glyoxylate and dicarboxylate metabolism, TCA cycle, starch and sucrose metabolism pathways in the Beagle dogs. A soluble guanylate cyclase activator, 4, 6-diamino-2-[1-(3-fluorothiophen-2-yl) methyl-1H-pyrazolo[3, 4-b]pyridin-3-yl] -5-pyrimidinyl-N-methyl methyl carbamate (sGC003), was administered (n=15) for comparison with the model and the control. We found that three groups were clearly clustered, indicating that there were differences in the three groups of metabolites. ANOVA statistical analysis results suggested that sGC003 exhibited pharmacodynamic effect, and at the same time, it also changed the endogenous metabolites to some extent. This study laid a foundation for the application of metabolomics in early diagnosis of pulmonary hypertension and provided experimental evidence for the application of sGC003 compound. In this study, the program of animal testing had been approved by Committee on the management of experimental animal in the Beijing Rixin Technology Co. Ltd.
Key words:    pulmonary hypertension    metabolomics    GC-TOF-MS    sGC003    endogenous metabolites   
收稿日期: 2019-03-11
DOI: 10.16438/j.0513-4870.2019-0170
基金项目: 国家科技重大专项课题资助项目(2015ZX09102003).
通讯作者: 史爱欣,Tel:86-10-85133632,E-mail:aixins0302@126.com
Email: aixins0302@126.com
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