Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery Diseases
Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery Diseases
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功能代谢组学表征了 N-乙酰神经氨酸在冠状动脉疾病中的关键作用
DOI：
10.1161/circulationaha.117.031139
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发表时间：
2018-03-27
期刊：
影响因子：
37.8
通讯作者：
Qi, Lian-Wen
中科院分区：
文献类型：
--
作者：
Zhang, Lei;Wei, Ting-Ting;Qi, Lian-Wen
背景：随着新的冠状动脉疾病（CAD）生物标志物通过代谢组学的出现，其潜在的功能机制仍有待阐明。功能代谢组学旨在将代谢组学衍生的生物标志物转化为疾病机制。方法：对来自4个独立中心的2324例接受冠状动脉造影的患者进行队列研究。在负离子模式下，超高效液相色谱和四极杆飞行时间质谱联用用于血浆中代谢物的非靶向分析。通过与冠心病类型（包括正常冠状动脉、非梗阻性冠状动脉粥样硬化、稳定型心绞痛、不稳定型心绞痛和急性心肌梗死）的交叉比较，发现了显著差异代谢物。随后，采用基于串联液相色谱-质谱的方法，使用同位素标记的标准添加对代谢标记物n -乙酰神经氨酸（Neu5Ac）进行了靶向分析。我们提出了一种功能代谢组学策略，通过体外和体内模型来研究Neu5Ac在CAD进展中的作用。结果：共鉴定出36种差异代谢物，其中35种与对照化合物确认。在中心1观察到冠心病进展期间血浆Neu5Ac升高（P=4.0 -64, n=2019），并在3个独立中心（n=305）重复。血浆中Neu5Ac水平升高通过精确的靶向定量证实。在机制上，Neu5Ac能够通过与RhoA和Cdc42结合激活Rho/Rho相关的含有螺旋的蛋白激酶信号通路，而不是与Rac1结合，从而在体外和体内触发心肌损伤。沉默调节Neu5Ac生成的神经氨酸酶-1，可以改善大鼠氧葡萄糖剥夺诱导的心肌细胞损伤和结扎/异丙肾上腺碱诱导的心肌缺血损伤。抗流感药物奥司他韦和扎那米韦对神经氨酸酶的药理抑制也能保护心肌细胞和心脏免受心肌损伤。结论：功能代谢组学鉴定了Neu5Ac在急性心肌梗死中的关键作用，靶向神经氨酸酶-1可能是CAD的一种未被认识的治疗干预措施。
Background: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims to translate metabolomics-derived biomarkers to disease mechanisms. Methods: A cohort of 2324 patients who underwent coronary angiography from 4 independent centers was studied. A combination of ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in the negative ion mode was used for untargeted analysis of metabolites in plasma. Significant differential metabolites were identified by cross-comparisons with and within CAD types, including normal coronary artery, nonobstructvie coronary atherosclerosis, stable angina, unstable angina, and acute myocardial infarction. A tandem liquid chromatography-mass spectrometry–based approach using isotope-labeled standard addition was subsequently performed for targeted analysis of the metabolic marker N-acetylneuraminic acid (Neu5Ac). A functional metabolomics strategy was proposed to investigate the role of Neu5Ac in the progression of CAD by using in vitro and in vivo models. Results: We identified a total of 36 differential metabolites, 35 of which were confirmed with reference compounds. Elevation of Neu5Ac was observed in plasma during CAD progression in center 1 (P=4.0e-64, n=2019) and replicated in 3 independent centers (n=305). The increased level of Neu5Ac in plasma was confirmed by accurate targeted quantification. Mechanistically, Neu5Ac was able to trigger myocardial injury in vitro and in vivo by activation of the Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding to RhoA and Cdc42, but not Rac1. Silencing neuraminidase-1, the enzyme that regulates Neu5Ac generation, ameliorated oxygen-glucose deprivation–induced injury in cardiomyocytes and ligation/isoprenaline-induced myocardial ischemia injury in rats. Pharmacological inhibition of neuraminidase by anti-influenza drugs, oseltamivir and zanamivir, also protected cardiomyocytes and the heart from myocardial injury. Conclusions: Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.