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Functional Metabolomics Characterizes a Key Role for N -Acetylneuraminic Acid in Coronary Artery Diseases

代谢组学 冠状动脉疾病 医学 体内 心肌梗塞 内科学 心脏病学 药理学 生物信息学 生物 生物技术
作者
Lei Zhang,Tingting Wei,Yong Li,Jing Li,Yong Fan,Feng-Qing Huang,Yuanyuan Cai,Gaoxiang Ma,Jinfeng Liu,Qianqian Chen,Shi-Lei Wang,Honglin Li,Raphael N. Alolga,Baolin Liu,Zhao Dong-sheng,Jianhua Shen,Xiangming Wang,Wei Zhu,Ping Li,Lian‐Wen Qi
出处
期刊:Circulation [Ovid Technologies (Wolters Kluwer)]
卷期号:137 (13): 1374-1390 被引量:148
标识
DOI:10.1161/circulationaha.117.031139
摘要

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.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.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.Functional metabolomics identified a key role for Neu5Ac in acute myocardial infarction, and targeting neuraminidase-1 may represent an unrecognized therapeutic intervention for CAD.
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