Rheumatology and Immunology Center, China Medical University Hospital, Taichung 404, Taiwan.
Translational Medicine Laboratory, China Medical University Hospital, Taichung 404, Taiwan.
Int J Mol Sci. 2021 Oct 22;22(21):11419. doi: 10.3390/ijms222111419.
Although the heterogeneity of high-density lipoprotein-cholesterol (HDL-c) composition is associated with atherosclerotic cardiovascular risk, the link between electronegative subfractions of HDL-c and atherosclerosis in rheumatoid arthritis (RA) remains unknown. We examined the association of the percentage of the most electronegative subfraction of HDL-c (H5%) and RA-related atherosclerosis. Using anion-exchange purification/fast-protein liquid chromatography, we demonstrated significantly higher H5% in patients (median, 7.2%) than HC (2.8%, < 0.005). Multivariable regression analysis revealed H5% as a significant predictor for subclinical atherosclerosis. We subsequently explored atherogenic role of H5 using cell-based assay. The results showed significantly higher levels of IL-1β and IL-8 mRNA in H5-treated (mean ± SD, 4.45 ± 1.22 folds, 6.02 ± 1.43-folds, respectively) than H1-treated monocytes (0.89 ± 0.18-folds, 1.03 ± 0.26-folds, respectively, both < 0.001). In macrophages, H5 upregulated the mRNA and protein expression of IL-1β and IL-8 in a dose-dependent manner, and their expression levels were significantly higher than H1-treated macrophages (all < 0.001). H5 induced more foam cell formation compared with H1-treated macrophages ( < 0.005). In addition, H5 has significantly lower cholesterol efflux capacity than H1 ( < 0.005). The results of nanoLC-MS/MS approach reveal that the best discriminator between high-H5% and normal-H5% is Apo(a), the main constituent of Lp(a). Moreover, Lp(a) level is a significant predictor for high-H5%. These observations suggest that H5 is involved in RA-related atherosclerosis.
虽然高密度脂蛋白胆固醇 (HDL-c) 组成的异质性与动脉粥样硬化性心血管风险相关，但 HDL-c 中的电负性亚组分与类风湿关节炎 (RA) 中的动脉粥样硬化之间的联系尚不清楚。我们研究了 HDL-c 中最电负性亚组分（H5%）的百分比与 RA 相关动脉粥样硬化之间的关联。使用阴离子交换纯化/快速蛋白液相色谱法，我们证明患者的 H5%明显高于 HC（中位数，7.2%比 2.8%， < 0.005）。多变量回归分析表明 H5%是亚临床动脉粥样硬化的重要预测指标。随后，我们使用基于细胞的测定法探索了 H5 的致动脉粥样硬化作用。结果显示，H5 处理的单核细胞中 IL-1β 和 IL-8 mRNA 水平明显更高（平均 ± SD，分别为 4.45 ± 1.22 倍和 6.02 ± 1.43 倍，均 < 0.001）。在巨噬细胞中，H5 以剂量依赖性方式上调 IL-1β 和 IL-8 的 mRNA 和蛋白表达，其表达水平明显高于 H1 处理的巨噬细胞（均 < 0.001）。与 H1 处理的巨噬细胞相比，H5 诱导更多泡沫细胞形成（ < 0.005）。此外，H5 的胆固醇流出能力明显低于 H1（ < 0.005）。nanoLC-MS/MS 方法的结果表明，高 H5%和正常 H5%之间的最佳区分物是 Apo(a)，即 Lp(a)的主要成分。此外，Lp(a)水平是高 H5%的重要预测指标。这些观察结果表明 H5 参与了 RA 相关的动脉粥样硬化。
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