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.
Department of Cardiology, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
J Am Coll Cardiol. 2017 Oct 17;70(16):2006-2019. doi: 10.1016/j.jacc.2017.08.053.
Nonenzymatic glycation of apolipoproteins plays a role in the pathogenesis of the vascular complications of diabetes.
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.
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.
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.
ApoA-IV glycation is associated with CAD severity in patients with T2DM, and g-apoA-IV induces atherogenesis through NR4A3 in apoE mice.
载脂蛋白的非酶糖基化在糖尿病血管并发症的发病机制中起作用。
本研究旨在探讨 2 型糖尿病（T2DM）患者的载脂蛋白（apo）A-IV 是否发生糖基化，以及 apoA-IV 糖基化是否与冠心病（CAD）有关。本研究还确定了糖基化 apoA-IV 的生物学效应。
本研究连续纳入 204 例无 CAD 的 T2DM 患者（I 组）、515 例有 CAD 的 T2DM 患者（II 组）和 176 例健康对照者（对照组）。apoA-IV 从超速离心分离的高密度脂蛋白中沉淀出来，并通过 Western 印迹密度测定法（apoA-IV 糖基化的相对强度）来确定其糖基化水平。在 37 名对照组、63 名 I 组和 138 名 II 组患者中，通过质谱鉴定 apoA-IV NƐ-（羧甲基）赖氨酸（CML）修饰位点。将生理盐水或由乙二醛培养生成的糖基化 apoA-IV（g-apoA-IV）注入载脂蛋白 E 小鼠以评估动脉粥样硬化形成，并用于细胞实验。
apoA-IV 糖基化的相对强度和丰度与 T2DM 患者 CAD 的存在和严重程度相关（均 p<0.05）。实验表明，g-apoA-IV 在体外引起促炎反应，并通过核受体 NR4A3 促进载脂蛋白 E 小鼠的动脉粥样硬化形成。在体外和体内，与高频率糖基化位点的突变（K-A）相比，g-apoA-IV 的致炎和致动脉粥样硬化作用较弱。
apoA-IV 糖基化与 T2DM 患者 CAD 的严重程度相关，g-apoA-IV 通过 apoE 小鼠中的 NR4A3 诱导动脉粥样硬化形成。
