Yang Dai1, Ying Shen2, Qing Run Li3, Feng Hua Ding2, Xiao Qun Wang1, Hong Juan Liu4, Xiao Xiang Yan1, Ling Jie Wang1, Ke Yang4, Hai Bo Wang4, Qiu Jing Chen2, Wei Feng Shen5, Rui Yan Zhang6, Lin Lu7. 1. 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. 2. Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China. 3. 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. 4. Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. 5. 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. 6. Institute of Cardiovascular Diseases, Shanghai Jiaotong University School of Medicine, Shanghai, China. Electronic address: zhangruiyan@263.net. 7. 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.
Abstract
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 NƐ-(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.
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 NƐ-(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.
Authors: Kristine Y Deleon-Pennell; Osasere K Ero; Yonggang Ma; Rugmani Padmanabhan Iyer; Elizabeth R Flynn; Ingrid Espinoza; Solomon K Musani; Ramachandran S Vasan; Michael E Hall; Ervin R Fox; Merry L Lindsey Journal: ACS Omega Date: 2019-01-15
Authors: Diana A Abbasi; Thu T A Nguyen; Deborah A Hall; Erin Robertson-Dick; Elizabeth Berry-Kravis; Stephanie M Cologna Journal: Cerebellum Date: 2021-05-27 Impact factor: 3.847