Association of carbamylated high-density lipoprotein with coronary artery disease in type 2 diabetes mellitus: carbamylated high-density lipoprotein of patients promotes monocyte adhesion.
Association of carbamylated high-density lipoprotein with coronary artery disease in type 2 diabetes mellitus: carbamylated high-density lipoprotein of patients promotes monocyte adhesion.
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氨甲酰化高密度脂蛋白与2型糖尿病冠状动脉疾病的关联：患者的氨甲酰化高密度脂蛋白促进单核细胞粘附。
DOI：
10.1186/s12967-020-02623-2
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发表时间：
2020-12-03
影响因子：
7.4
通讯作者：
Yang K
中科院分区：
文献类型：
--
作者：
Chen Z;Ding S;Wang YP;Chen L;Mao JY;Yang Y;Sun JT;Yang K
越来越多的证据表明，氨甲酰化脂蛋白加速动脉粥样硬化。然而，这种高密度脂蛋白（HDL）颗粒的修饰是否会改变2型糖尿病（T2 DM）患者的病情，并促进血管并发症的发生，目前尚不清楚。本研究旨在探讨2型糖尿病患者高密度脂蛋白（HDL）氨甲酰化水平的变化及其在动脉粥样硬化形成中的作用。共纳入148例接受血管造影的连续T2 DM患者和40例年龄和性别匹配的对照受试者。从血浆样品中分离HDL，并测量HDL氨甲酰赖氨酸（HDL-CBL）的浓度。此外，来自受试者的HDL和体外氨甲酰化HDL（C-HDL）与内皮细胞和单核细胞与内皮细胞粘附孵育。检测细胞粘附分子的表达及信号通路。2型糖尿病患者HDL-CBL水平显著高于对照组（6.13 ± 1.94 vs 12.00 ± 4.06（ng/mg），P < 0.001）。值得注意的是，HDL-CBL在伴冠状动脉疾病（CAD）的T2 DM患者（n = 102）中的增加比不伴CAD的患者（n = 46）更显著（12.75 ± 3.82 vs. 10.35 ± 4.11（ng/mg），P = 0.001）。多变量logistic回归分析表明，在调整确定的共同因素后，较高的HDL-CBL水平与糖尿病患者中较高的CAD患病率独立相关（调整后的比值比为1.174，95%置信区间为1.045-1.319，p = 0.017）。糖尿病合并冠心病组HDL对单核细胞粘附的促进作用显著高于非冠心病组和对照组（P < 0.001）。糖尿病HDL的这种促动脉粥样硬化能力与HDL-CBL水平呈正相关。此外，氨甲酰化高密度脂蛋白（C-HDL）与内皮细胞体外孵育可促进单核细胞与内皮细胞的粘附，诱导细胞粘附分子表达上调，并激活内皮细胞NF-κB/p65信号通路。抑制HDL的氨甲酰化或NF-κB的活化可减弱单核细胞与内皮细胞的粘附及细胞表面粘附分子的表达。我们的研究确定了2型糖尿病患者HDL的氨甲酰化修饰升高，特别是在合并CAD的患者中。我们还证明了C-HDL增强单核细胞与内皮细胞的粘附，表明C-HDL在T2 DM患者动脉粥样硬化中的潜在促动脉粥样硬化作用。试验注册https://register.clinicaltrials.gov，NCT 04390711于2020年5月14日注册; Retrophobic注册
Increasing evidence showed that carbamylated lipoprotein accelerated atherosclerosis. However, whether such modification of high-density lipoprotein (HDL) particles alters in type 2 diabetes mellitus (T2DM) patients and facilitates vascular complications remains unclear. We aimed to investigate the alteration of the carbamylation in HDL among T2DM patients and clarify its potential role in atherogenesis. A total of 148 consecutive T2DM patients undergoning angiography and 40 age- and gender-matched control subjects were included. HDL was isolated from plasma samples, and the concentration of HDL carbamyl-lysine (HDL-CBL) was measured. Furthermore, the HDL from subjects and in-vitro carbamylated HDL (C-HDL) was incubated with endothelial cells and monocyte to endothelial cell adhesion. Adhesion molecule expression and signaling pathway were detected. Compared with the control group, the HDL-CBL level was remarkably increased in T2DM patients (6.13 ± 1.94 vs 12.00 ± 4.06 (ng/mg), P < 0.001). Of note, HDL-CBL demonstrated a more significant increase in T2DM patients with coronary artery disease (CAD) (n = 102) than those without CAD (n = 46) (12.75 ± 3.82 vs. 10.35 ± 4.11(ng/mg), P = 0.001). Multivariate logistic regression analysis demonstrated that higher HDL-CBL level was independently associated with a higher prevalence of CAD in diabetic patients after adjusting for established cofounders (adjusted odds ratio 1.174, 95% confidence Interval 1.045–1.319, p = 0.017). HDL from diabetic patients with CAD enhanced greater monocyte adhesion than that from the non-CAD or the control group (P < 0.001). Such pro-atherogenic capacity of diabetic HDL positively correlated with HDL-CBL level. Furthermore, in-vitro incubation of carbamylated HDL (C-HDL) with endothelial promoted monocyte to endothelial cell adhesion, induced upregulation of cell adhesion molecules expression, and activated NF-κB/p65 signaling in endothelial cells. Inhibiting carbamylation of HDL or NF-κB activation attenuated the monocyte to endothelial cell adhesion and cell surface adhesion molecules expression. Our study identified elevated carbamylation modification of HDL from T2DM patients, especially in those with concomitant CAD. We also evidenced that C-HDL enhanced monocyte to endothelial cell adhesion, indicating a potential pro-atherogenic role of C-HDL in atherosclerosis among T2DM patients. Trial registration https://register.clinicaltrials.gov, NCT04390711 Registered on 14 May 2020; Retrospectively registered