异丙肾上腺素诱导心脏肥大大鼠的血清代谢组学研究

Serum metabolomics study of cardiac hypertrophy in an isoproterenol-induced rat model

目的通过血清代谢组寻找重要性生物标志物,探讨大鼠心脏肥大的发病机制。方法采用连续14 d腹腔注射异丙肾上腺素30 mg/(kg·d)建立大鼠心脏肥大模型。采用心脏重量指数评价大鼠心脏肥大模型。应用超高效液相色谱-四级杆-飞行时间串联质谱检测大鼠血清内源性代谢物,MPP软件分析代谢物差异,Human Metabolome Database (HMDB)数据库来确定生物标志物,MetaboAnalyst 4.0分析代谢通路。结果腹腔注射异丙肾上腺素可诱导大鼠心脏肥大。心脏肥大模型组与正常组具有明显的血清代谢产物差异,共鉴定10个潜在生物标志物。与正常组相比,心脏肥大模型组的鞘氨醇-1-磷酸和二高-γ-亚麻酸显著下调,D-果糖-1,6-二磷酸、脱氧腺嘌呤核苷、N-乙酰蛋氨酸、植物鞘氨醇、尿囊素、3-酮基-β-D-半乳糖、辛烷和甘油显著上调。结论异丙肾上腺素诱导的心脏肥大涉及鞘脂代谢、甘油脂代谢、半乳糖代谢、不饱和脂肪酸的生物合成及嘌呤代谢等代谢通路。本研究为揭示异丙肾上腺素诱导的心脏肥大循环血液的代谢变化提供参考。

Objective To screen potential biomarkers to explore the pathogenesis in a rat model of isoproterenolinduced cardiac hypertrophy. Methods Isoproterenol 30 mg/( kg·d) was used to establish the rat model of cardiac hypertrophy via intraperitoneal injection for 14 consecutive days. The rat cardiac hypertrophy model was evaluated via the cardiac index. Ultra high performance liquid chromatography-quadrupole-time of flight mass spectrometry( UHPLC-Q-TOFMS) was conducted to detect serum metabolites in normal and model rats. MPP software was used to analyze metabolic differences. The Human Metabolome Database( HMDB) was used to identify biomarkers. MetaboAnalyst 4. 0 was used to analyze metabolic pathways. Results Serum metabolites in the rats with isoproterenol-induced cardiac hypertrophy differed significantly from those of the normal rats,and 10 potential biomarkers were identified. Compared with the normal group,sphingosine 1-phosphate and dihomo-γ-linolenic acid in the model group were significantly downregulated,and D-fructose-1,6-bisphosphate,deoxyadenosine,N-acetylmethionine,phytosphingosine,allantoin,3-keto-β-D-galactose,octane,and glycerol were significantly upregulated. Conclusions The metabolic pathways involved in isoproterenol-induced cardiac hypertrophy include sphingolipid metabolism,glycerolipid metabolism,galactose metabolism,biosynthesis of unsaturated fatty acids,and purine metabolism. This study provides a basis for understanding the metabolic changes in the circulating blood in a model of isoproterenol-induced cardiac hypertrophy.