Glycated Apolipoprotein A-IV Induces Atherogenesis in Patients With CAD in Type 2 Diabetes
Glycated Apolipoprotein A-IV Induces Atherogenesis in Patients With CAD in Type 2 Diabetes
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糖化载脂蛋白 A-IV 诱导 2 型糖尿病 CAD 患者动脉粥样硬化
DOI：
10.1016/j.jacc.2017.08.053
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发表时间：
2017-10-17
影响因子：
24
通讯作者：
Lu, Lin
中科院分区：
文献类型：
--
作者：
Dai, Yang;Shen, Ying;Lu, Lin
背景载脂蛋白的非酶糖化在糖尿病血管并发症的发病机制中起着重要的作用。结论本研究调查了载脂蛋白（apo）A-IV在2型糖尿病（T2 DM）患者中是否发生糖化以及apoA-IV糖化是否与冠状动脉疾病（CAD）相关。研究还确定了糖化载脂蛋白A-IV的生物学效应。方法作者连续纳入204例T2 DM无CAD患者（组I），515例T2 DM伴CAD患者（组II），176例健康受试者（对照组）。从超离心分离的高密度脂蛋白中沉淀ApoA-IV，并基于蛋白质印迹光密度测定法（apoA-IV糖化的相对强度）测定其糖化水平。在37名对照受试者、63名I组患者和138名II组患者中，通过质谱法鉴定了ApoA-IV N-（羧甲基）赖氨酸（CML）修饰位点。结果apoA-IV糖基化的相对强度和丰度与T2 DM患者CAD的发生和严重程度相关（均P < 0.05）。实验表明，g-apoA-IV在体外诱导促炎反应，并通过核受体NR 4A 3促进apoE（-/-）小鼠的动脉粥样硬化形成。结论ApoA-IV糖基化与T2 DM患者CAD严重程度相关，在apoE（-/-）小鼠中，g-apoA-IV通过NR 4A 3诱导动脉粥样硬化形成。(C)2017年由美国心脏病学会基金会。
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 N epsilon-(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. (C) 2017 by the American College of Cardiology Foundation.