Metabolomic profiling of metoprolol-induced cardioprotection in a murine model of acute myocardial ischemia
Metabolomic profiling of metoprolol-induced cardioprotection in a murine model of acute myocardial ischemia
复制标题
急性心肌缺血小鼠模型中美托洛尔诱导的心脏保护作用的代谢组学分析
DOI：
10.1016/j.biopha.2020.109820
复制
发表时间：
2020-04-01
影响因子：
7.5
通讯作者：
Li, Fang
中科院分区：
文献类型：
--
作者：
Lai, Qiong;Yuan, Guangying;Li, Fang
美托洛尔(Met)在临床上广泛应用于心肌梗死、冠心病的治疗。然而，met操纵影响的体内代谢网络仍不清楚，除β1肾上腺素受体外，其治疗分子机制仍有待进一步阐明。在 ICR 小鼠中通过永久 CAL 24 小时诱导心肌梗塞 (MI)。检测心肌梗死面积、肌酸激酶（CK）、乳酸脱氢酶（LDH）、C反应蛋白（CRP）、肿瘤坏死因子-a（TNF-a）、心肌肌钙蛋白I（cTn-I）等生化指标、心功能及心肌病理变化，以确保Met对MI的改善。随后，利用HPLC-Q-TOF/MS通过代谢组学筛选并构建血清和尿液中发生显着变化的内源代谢物和网络。最后，根据筛选的差异代谢物和富集分析，通过蛋白质印迹和免疫组化筛选和验证可能成为Met新治疗靶点的潜在调节酶。 Met能有效缩小心肌梗死小鼠的梗死面积，改善生化指标，改善心功能和病理状况。我们的研究进一步发现，Met可以在MI病理条件下调节甘氨酸、丝氨酸和苏氨酸代谢、半胱氨酸和蛋氨酸代谢、嘌呤和嘧啶代谢途径。此外，包括 GATM、CSE 和 NT5E 在内的几种调节酶被证明受到 Met 的调节。本研究构建了Met的调控代谢网络图谱，阐明了Met调控的内源性代谢途径，验证了Met在心肌梗死中的新的潜在治疗靶点，为Met的临床应用提供进一步的参考。
Metoprolol (Met) is widely applied in the treatment of myocardial infarction and coronary heart disease in clinic. However, the metabolic network in vivo affected by met manipulation is still unclear and it's therapeutic molecular mechanisms were remained to be furthered elucidated except beta 1 adrenergic receptor. Myocardial infarction (MI) was induced by permanent CAL for 24 h in ICR mice. Myocardial infarct size, biochemical indicators such as creatine kinase (CK), lactate dehydrogenase (LDH), C-reactive Protein (CRP), tumor necrosis factor-a (TNF-a) and cardiac troponin I(cTn-I), cardiac function and myocardial pathological changes were detected to ensure the improvement of met on MI. Subsequently, the significantly changed endogenous metabolites and the network in both serum and urine were screened and constructed through metabolomics by using HPLC-Q-TOF/MS. Finally, the potential regulatory enzymes that could be the possible new therapeutic targets of Met were selected and validated by western blotting and immunohistochemistry based on the screened differential metabolites and the enrichment analysis. Met effectively reduced the infarct size of myocardial infarction mice, improved the biochemical indicators, and ameliorated the cardiac function and pathological conditions. Our study further found that Met could regulate the pathways of glycine, serine and threonine metabolism, cysteine and methionine metabolism, purine and pyrimidine metabolism under the pathological conditions of MI. Moreover, several regulatory enzymes involved GATM, CSE and NT5E were demonstrated to be regulated by Met. This study constructed the regulatory metabolic network map of Met, elucidated the endogenous metabolic pathway regulated by Met, and validated the new potential therapeutic targets of Met in MI, which might provide a further reference for the clinical application of Met.