PMID- 30092227 OWN - NLM STAT- MEDLINE DCOM- 20191213 LR - 20191217 IS - 1095-8584 (Electronic) IS - 0022-2828 (Linking) VI - 122 DP - 2018 Sep TI - Lysine glycation of apolipoprotein A-I impairs its anti-inflammatory function in type 2 diabetes mellitus. PG - 47-57 LID - S0022-2828(18)30734-X [pii] LID - 10.1016/j.yjmcc.2018.08.001 [doi] AB - Apolipoprotein A-I (apoA-I), the major protein compontent of high-density lipoprotein (HDL), exerts many anti-atherogenic functions. This study aimed to reveal whether nonenzymatic glycation of specific sites of apoA-I impaired its anti-inflammatory effects in type 2 diabetes mellitus (T2DM). LC-MS/MS was used to analyze the specific sites and the extent of apoA-I glycation either modified by glucose in vitro or isolated from T2DM patients. Cytokine release in THP-1 monocyte-derived macrophages was tested by ELISA. Activation of NF-kappa B pathway was detected by western blot. The binding affinity of apoA-I to THP-1 cells was measured using (125)I-labeled apoA-I. We identified seven specific lysine (Lys, K) residues of apoA-I (K12, K23, K40, K96, K106, K107 and K238) that were susceptible to be glycated either in vitro or in vivo. Glycation of apoA-I impaired its abilities to inhibit the release of TNF-alpha and IL-1beta against lipopolysaccharide (LPS) in THP-1 cells. Besides, the glycation levels of these seven K sites in apoA-I were inversely correlated with its anti-inflammatory abilities. Furthermore, glycated apoA-I had a lower affinity to THP-1 cells than native apoA-I had. We generated mutant apoA-I (K107E, M-apoA-I) with a substitution of glutamic acid (Glu, E) for lysine at the 107th site, and found that compared to wild type apoA-I (WT-apoA-I), M-apoA-I decreased its anti-inflammatory effects in THP-1 cells. We also modeled the location of these seven K residues on apoA-I which allowed us to infer the conformational alteration of glycated apoA-I and HDL. In summary, glycation of these seven K residues altered the conformation of apoA-I and consequently impaired the protective effects of apoA-I, which may partly account for the increased risk of cardiovascular disease (CVD) in diabetic subjects. CI - Copyright (c) 2018. Published by Elsevier Ltd. FAU - Liu, Donghui AU - Liu D AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China; Department of Cardiology, the Affiliated Cardiovascular Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, Fujian 361004, China. FAU - Ji, Liang AU - Ji L AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China. FAU - Zhao, Mingming AU - Zhao M AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China. FAU - Wang, Yang AU - Wang Y AD - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. FAU - Guo, Yansong AU - Guo Y AD - Department of Cardiovascular Medicine, Fujian Provincial Hospital, Fuzhou, China. FAU - Li, Ling AU - Li L AD - Proteomics Laboratory, Cleveland Clinic, Cleveland, OH 44195, USA. FAU - Zhang, Dongmei AU - Zhang D AD - Proteomics Laboratory, Cleveland Clinic, Cleveland, OH 44195, USA. FAU - Xu, Liang AU - Xu L AD - Department of Cardiology, the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China. FAU - Pan, Bing AU - Pan B AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China. FAU - Su, Jinzi AU - Su J AD - Department of Cardiology, the First Affiliated Hospital of Fujian Medical University, Fujian 350005, China. FAU - Xiang, Song AU - Xiang S AD - Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, 294 Taiyuan Road, Shanghai 200031, China. FAU - Pennathur, Subramaniam AU - Pennathur S AD - Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA. FAU - Li, Jingxuan AU - Li J AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China. FAU - Gao, Jianing AU - Gao J AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China. FAU - Liu, Pingsheng AU - Liu P AD - National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China. FAU - Willard, Belinda AU - Willard B AD - Proteomics Laboratory, Cleveland Clinic, Cleveland, OH 44195, USA. Electronic address: willarb@ccf.org. FAU - Zheng, Lemin AU - Zheng L AD - The Institute of Cardiovascular Sciences, Institute of Systems Biomedicine, School of Basic Medical Sciences, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing Key Laboratory of Cardiovascular Receptors Research, Peking University Health Science Center, 100191 Beijing, China. Electronic address: zhengl@bjmu.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180807 PL - England TA - J Mol Cell Cardiol JT - Journal of molecular and cellular cardiology JID - 0262322 RN - 0 (APOA1 protein, human) RN - 0 (Apolipoprotein A-I) RN - 0 (Interleukin-1beta) RN - 0 (Lipopolysaccharides) RN - 0 (Lipoproteins, HDL) RN - 0 (NF-kappa B) RN - 0 (TNF protein, human) RN - 0 (Tumor Necrosis Factor-alpha) RN - 3KX376GY7L (Glutamic Acid) RN - EC 5.3.4.1 (Protein Disulfide-Isomerases) RN - IY9XDZ35W2 (Glucose) RN - K3Z4F929H6 (Lysine) SB - IM MH - Aged MH - Amino Acid Substitution MH - Analysis of Variance MH - Apolipoprotein A-I/*metabolism MH - Chromatography, Liquid MH - Diabetes Mellitus, Type 2/*blood MH - Glucose MH - Glutamic Acid/genetics MH - Glycosylation MH - Humans MH - Inflammation/*metabolism MH - Interleukin-1beta/metabolism MH - Lipopolysaccharides/pharmacology MH - Lipoproteins, HDL/metabolism MH - Lysine/genetics/*metabolism MH - Middle Aged MH - NF-kappa B/metabolism MH - Protein Conformation MH - Protein Disulfide-Isomerases MH - THP-1 Cells MH - Tandem Mass Spectrometry MH - Tumor Necrosis Factor-alpha/metabolism OTO - NOTNLM OT - Apolipoprotein OT - Glycation OT - HDL OT - Inflammation OT - Proteomics EDAT- 2018/08/10 06:00 MHDA- 2019/12/18 06:00 CRDT- 2018/08/10 06:00 PHST- 2018/04/09 00:00 [received] PHST- 2018/07/22 00:00 [revised] PHST- 2018/08/01 00:00 [accepted] PHST- 2018/08/10 06:00 [pubmed] PHST- 2019/12/18 06:00 [medline] PHST- 2018/08/10 06:00 [entrez] AID - S0022-2828(18)30734-X [pii] AID - 10.1016/j.yjmcc.2018.08.001 [doi] PST - ppublish SO - J Mol Cell Cardiol. 2018 Sep;122:47-57. doi: 10.1016/j.yjmcc.2018.08.001. Epub 2018 Aug 7.