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

• DOI: 10.1161/circulationaha.117.031139
• Publication Date: 2017-12-06T10:15:14Z
• Authors: Lei Zhang; Ting-Ting Wei; Yong Li; Jing Li; Yong Fan; Feng-Qing Huang; Yuan-Yuan Cai; Gaoxiang Ma; Jin-Feng Liu; Qian-Qian Chen; Shi-Lei Wang; Honglin Li; Raphael N. Alolga; Baolin Liu; Dong-Sheng Zhao; Jian-Hua Shen; Xiang-Ming Wang; Wei Zhu; Ping Li; Lian-Wen Qi
• Keywords: Male; 0301 basic medicine; Cell Survival; Neuraminidase; Coronary Artery Disease; Coronary Angiography; N-Acetylneuraminic Acid; Rats; 3. Good health; Rats, Sprague-Dawley; 03 medical and health sciences; Oseltamivir; Animals; Humans; Metabolomics; Myocytes, Cardiac; RNA Interference; RNA, Small Interfering; cdc42 GTP-Binding Protein; rhoA GTP-Binding Protein; Biomarkers; Protein Binding

Background: As new biomarkers of coronary artery diseases (CAD) emerge via metabolomics, the underlying functional mechanisms remain to be elucidated. Functional metabolomics aims translate metabolomics-derived disease mechanisms. Methods: A cohort 2324 patients who underwent angiography from 4 independent centers was studied. combination ultra–performance liquid chromatography and quadrupole time-of-flight mass spectrometry in negative ion mode used for untargeted analysis metabolites plasma. Significant differential were identified by cross-comparisons with within CAD types, including normal artery, nonobstructvie atherosclerosis, stable angina, unstable acute myocardial infarction. tandem chromatography-mass spectrometry–based approach using isotope-labeled standard addition subsequently performed targeted metabolic marker N -acetylneuraminic acid (Neu5Ac). strategy proposed investigate role Neu5Ac progression vitro vivo models. Results: We a total 36 metabolites, 35 which confirmed reference compounds. Elevation observed plasma during center 1 ( P =4.0e-64, n=2019) replicated 3 (n=305). The increased level accurate quantification. Mechanistically, able trigger injury activation Rho/Rho-associated coiled-coil containing protein kinase signaling pathway through binding RhoA Cdc42, but not Rac1. Silencing neuraminidase-1, enzyme that regulates generation, ameliorated oxygen-glucose deprivation–induced cardiomyocytes ligation/isoprenaline-induced ischemia rats. Pharmacological inhibition neuraminidase anti-influenza drugs, oseltamivir zanamivir, also protected heart injury. Conclusions: key infarction, targeting neuraminidase-1 may represent an unrecognized therapeutic intervention CAD.