Department of Cardiology, Ruijin Hospital, Jiao Tong University School of Medicine, No. 197, Ruijin Er Road, Huangpu District, Shanghai, 200025, China.
Institute of Cardiovascular Disease, Jiao Tong University School of Medicine, Shanghai, 200025, China.
J Transl Med. 2017 Nov 10;15(1):234. doi: 10.1186/s12967-017-1336-z.
Biomarkers of early plaque progression are still elusive. Myeloid DAP12-associating lectin-1 (MDL-1), also called CLEC5A, is a C-type lectin receptor implicated in the progression of multiple acute and chronic inflammatory diseases. However, the relationship between its level and atherosclerosis is unknown. In this study, we aimed to investigate the correlation between macrophage MDL-1 expression and early atherosclerosis progression.
Immunofluorescence staining, real-time PCR and western blot were performed to analyze MDL-1 expression in aorta or mice macrophages. The role of MDL-1 in macrophage survival was further investigated by adenovirus infection and TUNEL assay.
Significant MDL-1 expression was found in advanced human and apoE-/- mice atherosclerotic plaques, especially in lesional macrophages. In the model of atherosclerosis regression, we found MDL-1 expression was highly downregulated in lesional macrophages from ldlr-/- mouse regressive plaques, coincident with a reduction in lesional macrophage content and marker of M1 proinflammatory macrophages. Furthermore, we found MDL-1 was significantly expressed in inflammatory M1 subtype polarized bone marrow-derived macrophages. In vitro experiments, the level of MDL-1 was remarkably elevated in macrophages treated with pathophysiological drivers of plaque progression, such as oxidized low-density lipoprotein (ox-LDL) and hypoxia. Mechanistically, we demonstrated that MDL-1 overexpression notably promoted macrophage survival and decreased cleaved caspase-3 expression under ox-LDL stimulation, which suggested that it could maintain lesional macrophage survival and cause its accumulation.
This study firstly demonstrated that MDL-1 is mainly expressed in atherosclerotic lesional macrophages and increased macrophage MDL-1 expression is associated with early plaque progression and promotes macrophage survival.
早期斑块进展的生物标志物仍然难以捉摸。髓样 DAP12 相关凝集素-1（MDL-1），也称为 CLEC5A，是一种 C 型凝集素受体，与多种急性和慢性炎症性疾病的进展有关。然而，其水平与动脉粥样硬化之间的关系尚不清楚。在这项研究中，我们旨在研究巨噬细胞 MDL-1 表达与早期动脉粥样硬化进展之间的相关性。
通过免疫荧光染色、实时 PCR 和 Western blot 分析主动脉或小鼠巨噬细胞中 MDL-1 的表达。通过腺病毒感染和 TUNEL 测定进一步研究 MDL-1 在巨噬细胞存活中的作用。
在人动脉粥样硬化斑块和 apoE-/- 小鼠的晚期斑块中发现了明显的 MDL-1 表达，尤其是在病变巨噬细胞中。在动脉粥样硬化消退模型中，我们发现 ldlr-/- 小鼠消退斑块中的病变巨噬细胞中 MDL-1 表达显著下调，与病变巨噬细胞含量和 M1 促炎巨噬细胞标志物减少相一致。此外，我们发现 MDL-1 在炎症性 M1 亚型极化的骨髓来源巨噬细胞中显著表达。在体外实验中，用病理生理学驱动斑块进展的物质（如氧化低密度脂蛋白[ox-LDL]和缺氧）处理的巨噬细胞中 MDL-1 水平显著升高。机制上，我们证明在 ox-LDL 刺激下，MDL-1 过表达显著促进巨噬细胞存活并降低裂解的 caspase-3 表达，这表明它可以维持病变巨噬细胞的存活并导致其积累。
本研究首次证明 MDL-1 主要表达在动脉粥样硬化病变巨噬细胞中，增加巨噬细胞 MDL-1 表达与早期斑块进展相关，并促进巨噬细胞存活。
