PMID- 29025558 OWN - NLM STAT- MEDLINE DCOM- 20171019 LR - 20171019 IS - 1558-3597 (Electronic) IS - 0735-1097 (Linking) VI - 70 IP - 16 DP - 2017 Oct 17 TI - Glycated Apolipoprotein A-IV Induces Atherogenesis in Patients With CAD in Type 2 Diabetes. PG - 2006-2019 LID - S0735-1097(17)39385-3 [pii] LID - 10.1016/j.jacc.2017.08.053 [doi] AB - BACKGROUND: Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes. OBJECTIVES: This study investigated whether apolipoprotein (apo) A-IV was glycated in patients with type 2 diabetes mellitus (T2DM) and whether apoA-IV glycation was related to coronary artery disease (CAD). The study also determined the biological effects of glycated apoA-IV. METHODS: The authors consecutively enrolled 204 patients with T2DM without CAD (Group I), 515 patients with T2DM with CAD (Group II), and 176 healthy subjects (control group) in this study. ApoA-IV was precipitated from ultracentrifugally isolated high-density lipoprotein, and its glycation level was determined based on Western blotting densitometry (relative intensity of apoA-IV glycation). ApoA-IV NE-(carboxylmethyl) lysine (CML) modification sites were identified by mass spectrometry in 37 control subjects, 63 patients in Group I, and 138 patients in Group II. Saline or glycated apoA-IV (g-apoA-IV) generated by glyoxal culture was injected into apoE(-/-) mice to evaluate atherogenesis, and was also used for the cell experiments. RESULTS: The relative intensity and the abundance of apoA-IV glycation were associated with the presence and severity of CAD in patients with T2DM (all p < 0.05). The experiments showed that g-apoA-IV induced proinflammatory reactions in vitro and promoted atherogenesis in apoE(-/-) mice through the nuclear receptor NR4A3. G-apoA-IV with mutations (K-A) at high-frequency glycation sites exhibited more weakened proinflammatory and atherogenic effects than did g-apoA-IV both in vitro and in vivo. CONCLUSIONS: ApoA-IV glycation is associated with CAD severity in patients with T2DM, and g-apoA-IV induces atherogenesis through NR4A3 in apoE(-/-) mice. CI - Copyright (c) 2017 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved. FAU - Dai, Yang AU - Dai Y AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Shen, Ying AU - Shen Y AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Li, Qing Run AU - Li QR AD - CAS Key Laboratory of Systems Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. FAU - Ding, Feng Hua AU - Ding FH AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Wang, Xiao Qun AU - Wang XQ AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Liu, Hong Juan AU - Liu HJ AD - Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Yan, Xiao Xiang AU - Yan XX AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Wang, Ling Jie AU - Wang LJ AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Yang, Ke AU - Yang K AD - Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Wang, Hai Bo AU - Wang HB AD - Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Chen, Qiu Jing AU - Chen QJ AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. FAU - Shen, Wei Feng AU - Shen WF AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: rjshenweifeng@126.com. FAU - Zhang, Rui Yan AU - Zhang RY AD - Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: zhangruiyan@263.net. FAU - Lu, Lin AU - Lu L AD - Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China; Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: rjlulin1965@163.com. LA - eng PT - Journal Article PL - United States TA - J Am Coll Cardiol JT - Journal of the American College of Cardiology JID - 8301365 RN - 0 (Apolipoproteins A) RN - 0 (Biomarkers) RN - 0 (apolipoprotein A-IV) SB - IM CIN - J Am Coll Cardiol. 2017 Oct 17;70(16):2020-2021. PMID: 29025559 MH - Aged MH - Animals MH - Apolipoproteins A/isolation & purification/*metabolism MH - Atherosclerosis/diagnostic imaging/epidemiology/*metabolism MH - Biomarkers/metabolism MH - Coronary Angiography/methods MH - Coronary Artery Disease/diagnostic imaging/epidemiology/*metabolism MH - Diabetes Mellitus, Type 2/diagnostic imaging/epidemiology/*metabolism MH - Female MH - Glycosylation MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Middle Aged OTO - NOTNLM OT - NR4A3 OT - apolipoprotein A-IV OT - atherogenesis OT - diabetes OT - glycation EDAT- 2017/10/14 06:00 MHDA- 2017/10/20 06:00 CRDT- 2017/10/14 06:00 PHST- 2017/04/05 00:00 [received] PHST- 2017/08/15 00:00 [revised] PHST- 2017/08/21 00:00 [accepted] PHST- 2017/10/14 06:00 [entrez] PHST- 2017/10/14 06:00 [pubmed] PHST- 2017/10/20 06:00 [medline] AID - S0735-1097(17)39385-3 [pii] AID - 10.1016/j.jacc.2017.08.053 [doi] PST - ppublish SO - J Am Coll Cardiol. 2017 Oct 17;70(16):2006-2019. doi: 10.1016/j.jacc.2017.08.053.