文献类型：期刊文献

英文题名：Functional Metabolomics Characterizes a Key Role for N-Acetylneuraminic Acid in Coronary Artery Diseases

作者：Zhang, Lei[3];Wei, Ting-Ting[3];Li, Yong[4];Li, Jing[1];Fan, Yong[3];Huang, Feng-Qing[3];Cai, Yuan-Yuan[1];Ma, Gaoxiang[1];Liu, Jin-Feng[3];Chen, Qian-Qian[3];Wang, Shi-Lei[3];Li, Honglin[5];Alolga, Raphael N.[3];Liu, Baolin[1];Zhao, Dong-Sheng[6];Shen, Jian-Hua[7];Wang, Xiang-Ming[8];Zhu, Wei[2];Li, Ping[3];Qi, Lian-Wen[1,3]

机构：[1]China Pharmaceut Univ, Clin Metabol Ctr, 639 Longmian Rd, Nanjing 211198, Jiangsu, Peoples R China;[2]Nanjing Med Univ, Affiliated Hosp 1, Dept Oncol, 300 Guangzhou Rd, Nanjing 210029, Jiangsu, Peoples R China;[3]China Pharmaceut Univ, State Key Lab Nat Med, Sch Tradit Chinese Pharm, Nanjing, Jiangsu, Peoples R China;[4]Jiangsu Univ, Afliated Wujin Hosp, Dept Cardiol, Changzhou, Peoples R China;[5]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, Shanghai, Peoples R China;[6]Nantong Univ, Dept Cardiol, Affiliated Hosp 2, Nantong, Peoples R China;[7]Northern Jiangsu Peoples Hosp, Dept Cardiol, Yangzhou, Jiangsu, Peoples R China;[8]Nanjing Med Univ, Affiliated Hosp 1, Dept Geriatr Cardiol, Nanjing, Jiangsu, Peoples R China

年份：2018

卷号：137

期号：13

起止页码：1374

外文期刊名：CIRCULATION

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000429061100012)】；

基金：This study was supported in part by the Major Research Plan of the National Science Foundation of China (Grant No. 91639115), National Natural Science Foundation of China (81222052, 81421005, 31370505, and 31670495), and Natural Science Foundation of Jiangsu province (BK20170737).

语种：英文

外文关键词：biomarkers; cardiovascular diseases; coronary artery disease; metabolomics; myocardial ischemia; neuraminidase

摘要：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.