低密度脂蛋白在系统性红斑狼疮相关早期血管老化中的作用。

Role of Low-Density Lipoprotein in Early Vascular Aging Associated With Systemic Lupus Erythematosus.

机构信息

Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan, and Texas Heart Institute, Houston.

Kaohsiung Medical University, Kaohsiung, Taiwan, and Texas Heart Institute, Houston.

出版信息

Arthritis Rheumatol. 2020 Jun;72(6):972-984. doi: 10.1002/art.41213. Epub 2020 Apr 30.

DOI:10.1002/art.41213

PMID:31994323

Abstract

OBJECTIVE

Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients.

METHODS

Plasma LDL from 45 SLE patients (SLE-LDL) and from 37 normal healthy controls (N-LDL) was chromatographically divided into 5 subfractions (L1-L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid-mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE mice.

RESULTS

The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE-L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima-media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and in the SLE-L5 plasma subfraction. Injecting SLE-LDL, SLE-L5, or LPC into young, male apoE mice caused increases in plasma CX3CL1 levels, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N-LDL or SLE-L1 had negligible effects (n = 3-8 mice per group). In vitro, SLE-L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE-LDL and SLE-L5 induced the expression of CX3CL1 and enhanced monocyte-endothelial cell adhesion in assays with bovine aortic endothelial cells.

CONCLUSION

An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.

摘要

目的

红斑狼疮（SLE）患者常常在年轻时就出现动脉粥样硬化并发症，但 LDL 水平正常。本研究旨在探讨 LDL 组成在促进 SLE 患者早期血管老化中的作用。

方法

将 45 例 SLE 患者（SLE-LDL）和 37 例正常健康对照者（N-LDL）的血浆 LDL 进行色谱分离成 5 个亚组分（L1-L5），并分析亚组分组成。评估亚组分水平与早期血管老化征象之间的相关性。采用体外测定和载脂蛋白 E （apoE）小鼠实验研究脂质介导的内皮功能障碍的机制。

结果

与正常对照组相比，SLE 患者血浆中 L5 百分比增加了 3.4 倍。SLE-L5 中这种增加的百分比与平均血压（r = 0.27，P = 0.04）、颈动脉内膜中层厚度（右侧颈动脉 IMT，r = 0.4，P = 0.004；左侧颈动脉 IMT，r = 0.36，P = 0.01）、脉搏波速度（r = 0.29，P = 0.04）和 SLE 患者血液中 CD16+单核细胞（r = 0.35，P = 0.004）和 CX3CL1 细胞因子（r = 0.43，P < 0.001）水平呈正相关。基质辅助激光解吸电离飞行时间质谱分析显示，SLE-LDL 和 SLE-L5 血浆亚组分中溶血磷脂酰胆碱（LPC）和血小板活化因子（PAF）的水平升高。向年轻雄性 apoE 小鼠注射 SLE-LDL、SLE-L5 或 LPC 会导致血浆 CX3CL1 水平升高、主动脉脂肪条纹面积增加、主动脉血管老化以及巨噬细胞浸润主动脉壁，而注射 N-LDL 或 SLE-L1 则几乎没有影响（每组 3-8 只小鼠）。体外，SLE-L5 脂质提取物诱导人单核细胞中 CX3CR1 和 CD16 的表达增加；合成 PAF 和 LPC 也有类似作用。此外，SLE-LDL 和 SLE-L5 的脂质提取物诱导 CX3CL1 的表达，并增强牛主动脉内皮细胞中单核细胞-内皮细胞的黏附。