Department of Internal Medicine/Cardiology, Heart Center Leipzig at University of Leipzig, Strümpellstr. 39, 04289, Leipzig, Germany.
Institute of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany.
Heart Vessels. 2022 Jan;37(1):161-171. doi: 10.1007/s00380-021-01908-w. Epub 2021 Aug 30.
High-density lipoprotein (HDL), best known for cholesterol transport, also has anti-inflammatory effects. Previous studies suggest involvement of myeloperoxidase (MPO) in modification of HDL. HDL bound Sphingosine-1-phosphate (S1P) has been implied to be an essential protein regarding beneficial HDL effects. In this study, we analyzed anti-inflammatory HDL properties in patients with atrial fibrillation (AF), a disease involving atrial inflammation, compared to non-AF controls and whether anti-inflammatory properties improve upon catheter ablation. Additionally, association with serum concentrations of MPO and S1P were assessed. We isolated HDL from 25 AF patients, 13 non-AF individuals and 14 AF patients at follow-up (FU) after catheter ablation. S1P was measured in a cohort of 141 AF and 21 FU patients. Following preincubation with HDL from either group, bovine aortic endothelial cells were stimulated using tumor necrosis factor α and expression of pro-inflammatory genes intercellular adhesion molecule 1 (ICAM1), vascular cell adhesion molecule 1 (VCAM1), E-selectin (SELE) and P-selectin (SELP) was assessed using qPCR. Concentrations of circulating protein of these genes as well as MPO and S1P were measured in serum samples. Compared to non-AF individuals HDL from AF patients suppressed gene expression of the pro-inflammatory adhesion molecules ICAM1, VCAM1, SELE and SELP 27%, 18%, 21% and 57% less, respectively (p < 0.05 for all except SELE p = 0.06). In FU patients, the anti-inflammatory HDL activity was improved (suppression of ICAM1 + 22%, VCAM1 + 10%, SELE + 38% and SELP + 75%, p < 0.05 for all except VCAM1 p = 0.08). AF patients using angiotensin converting enzyme inhibitors or angiotensin receptor blockers had better anti-inflammatory HDL properties than non-users (gene expression suppression at least 28% more, p < 0.05 for all except ICAM1 p = 0.051). Circulating protein concentrations were not correlated with in vitro gene-expression, but circulating P-selectin was generally elevated in AF and FU patients compared to non-AF patients. MPO plasma concentration was positively associated with gene-expression of ICAM1, VCAM1 and SELP (r > 0.4, p < 0.05). Serum concentrations of S1P were increased in FU patients {1.201 µM [1.077-1.543]} compared to AF patients {0.953 µM [0.807-1.135], p < 0.01} but not correlated with ICAM1, VCAM1 and SELP gene expression. We conclude that the anti-inflammatory activity of HDL is impaired in AF patients, which might promote AF progression and AF-associated complications.
高密度脂蛋白（HDL）以胆固醇转运而闻名，也具有抗炎作用。先前的研究表明，髓过氧化物酶（MPO）参与了 HDL 的修饰。结合神经鞘氨醇-1-磷酸（S1P）的 HDL 被认为是与有益的 HDL 作用相关的必需蛋白。在这项研究中，我们分析了与心房颤动（AF）患者的抗炎 HDL 特性，与非 AF 对照组相比，以及导管消融后抗炎特性是否改善。此外，还评估了与血清 MPO 和 S1P 浓度的相关性。我们从 25 例 AF 患者、13 例非 AF 个体和 14 例 AF 患者在导管消融后的随访（FU）中分离出 HDL。在 141 例 AF 和 21 例 FU 患者的队列中测量了 S1P。在用来自任何一组的 HDL 进行预孵育后，使用肿瘤坏死因子 α 刺激牛主动脉内皮细胞，并使用 qPCR 评估促炎基因细胞间粘附分子 1（ICAM1）、血管细胞粘附分子 1（VCAM1）、E-选择素（SELE）和 P-选择素（SELP）的基因表达。还测量了血清样本中这些基因以及 MPO 和 S1P 的循环蛋白浓度。与非 AF 个体相比，来自 AF 患者的 HDL 分别抑制了促炎粘附分子 ICAM1、VCAM1、SELE 和 SELP 的基因表达 27%、18%、21%和 57%（除 SELE 外，所有 p 值均 < 0.05，p = 0.06）。在 FU 患者中，抗炎 HDL 活性得到改善（ICAM1 抑制+22%，VCAM1 抑制+10%，SELE 抑制+38%和 SELP 抑制+75%，所有 p 值均 < 0.05，除 VCAM1 外，p = 0.08）。使用血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂的 AF 患者比非使用者具有更好的抗炎 HDL 特性（抑制基因表达至少增加 28%，所有 p 值均 < 0.05，除 ICAM1 外，p = 0.051）。循环蛋白浓度与体外基因表达不相关，但 AF 和 FU 患者的循环 P-选择素一般高于非 AF 患者。MPO 血浆浓度与 ICAM1、VCAM1 和 SELP 的基因表达呈正相关（r > 0.4，p < 0.05）。与 AF 患者相比，FU 患者的 S1P 血清浓度升高{1.201 μM [1.077-1.543]}，p < 0.01，但与 ICAM1、VCAM1 和 SELP 的基因表达不相关。我们得出结论，AF 患者的 HDL 抗炎活性受损，这可能促进 AF 进展和 AF 相关并发症。
