Mol Barend M, Motsak Tetiana, Hoekstra Joost K R, Zuluaga Valentina Osorio, Rumpff-Derksen Saskia, Paspali-Strik Ioanna, Ngan Sofong Cam, Pasterkamp Gerard, de Borst Gert J, Sze Siu Kwan, de Kleijn Dominique P V
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands.
Department of Vascular Surgery, University Medical Centre Utrecht, Utrecht, the Netherlands; Department Internal Medicine, Bogomolets National Medical University, Kyiv, Ukraine.
Eur J Vasc Endovasc Surg. 2025 May 7. doi: 10.1016/j.ejvs.2025.04.067.
Macrophage influx is an important feature of human plaque destabilisation. Studies in mice suggest a role of the isoD(Asp)G(Gly)R(Arg) three amino acid motif in fibronectin (isoDGR-modified fibronectin) in macrophage influx. The association between isoDGR fibronectin in human plasma and plaque with plaque macrophage influx and vulnerable plaque characteristics has not been investigated in large human cohorts.
Levels of isoDGR fibronectin were measured in individual plasma and plaques from carotid endarterectomy (CEA) patients from the Athero-Express biobank and associated with macrophage content and other vulnerable plaque characteristics in the carotid plaque of the same patient. Levels of isoDGR fibronectin were measured using an enzyme linked immunosorbent assay. Carotid plaque characteristics were visualised with immunohistochemistry staining and scored semi-quantitatively. Baseline characteristics were analysed with Pearson's chi squared test and Mann-Whitney U test when applicable. Uni- and multivariable logistic regression analyses were used to identify associations with adverse plaque characteristics.
Plasma isoDGR fibronectin was measured in 730 CEA patients (12.3% asymptomatic). Patients with moderate or heavy plaque macrophage staining had higher levels of isoDGR fibronectin than patients with no or minor macrophage staining (multivariable odds ratio [OR] 1.40, 95% confidence interval [CI] 1.04 - 1.90; p = .028). Of the 730 CEA patients, 348 had plaque samples available for isoDGR fibronectin measurements. In the multivariable analysis, higher plaque levels of isoDGR fibronectin were associated with moderate or high plaque macrophage staining (OR 1.22, 95% CI 1.00 - 1.56; p = .049), > 40% plaque area of fat (OR 1.44, 95% CI 1.14 - 1.86; p = .004), and intraplaque haemorrhage (OR 1.38, 95% 1.12 - 1.72; p = .003).
In this large human cohort study, high plasma and plaque levels of isoDGR fibronectin were associated with more plaque macrophages and other adverse plaque characteristics. This suggests the involvement of isoDGR fibronectin in human plaque destabilisation and blocking isoDGR modifications as a potential treatment modality.
巨噬细胞浸润是人类斑块不稳定的一个重要特征。对小鼠的研究表明，纤连蛋白中的异天冬氨酸-甘氨酸-精氨酸（isoDGR）三氨基酸基序（isoDGR修饰的纤连蛋白）在巨噬细胞浸润中起作用。人类血浆中的isoDGR纤连蛋白与斑块、斑块巨噬细胞浸润及易损斑块特征之间的关联尚未在大型人类队列中进行研究。
在动脉粥样硬化表达生物样本库的颈动脉内膜切除术（CEA）患者的个体血浆和斑块中测量isoDGR纤连蛋白水平，并将其与同一患者颈动脉斑块中的巨噬细胞含量及其他易损斑块特征相关联。使用酶联免疫吸附测定法测量isoDGR纤连蛋白水平。通过免疫组织化学染色观察颈动脉斑块特征并进行半定量评分。适用时，使用Pearson卡方检验和Mann-Whitney U检验分析基线特征。采用单变量和多变量逻辑回归分析来确定与不良斑块特征的关联。
对730例CEA患者（12.3%无症状）的血浆isoDGR纤连蛋白进行了测量。中度或重度斑块巨噬细胞染色的患者比无或轻度巨噬细胞染色的患者具有更高水平的isoDGR纤连蛋白（多变量优势比[OR]1.40，95%置信区间[CI]1.04 - 1.90；p = 0.028）。在730例CEA患者中，348例有可用于测量isoDGR纤连蛋白的斑块样本。在多变量分析中，较高的斑块isoDGR纤连蛋白水平与中度或高度斑块巨噬细胞染色（OR 1.22，95% CI 1.00 - 1.56；p = 0.049）、脂肪斑块面积>40%（OR 1.44，95% CI 1.14 - 1.86；p = 0.004）以及斑块内出血（OR 1.38，95% 1.12 - 1.72；p = 0.003）相关。
在这项大型人类队列研究中，高血浆和斑块水平的isoDGR纤连蛋白与更多的斑块巨噬细胞及其他不良斑块特征相关。这表明isoDGR纤连蛋白参与了人类斑块的不稳定过程，并且阻断isoDGR修饰作为一种潜在的治疗方式。
