半乳糖凝集素-3 通过 LOX-1 介导的信号通路加重 ox-LDL 诱导的内皮功能障碍。
Galectin-3 aggravates ox-LDL-induced endothelial dysfunction through LOX-1 mediated signaling pathway.
机构信息
Department of Physical Therapy, College of Medical and Health Science, Asia University, Taichung, Taiwan.
Department of Physical Therapy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
出版信息
Environ Toxicol. 2019 Jul;34(7):825-835. doi: 10.1002/tox.22750. Epub 2019 Apr 9.
Galectin-3, a biomarker linking oxidative stress and inflammation, participates in different mechanisms related to atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Accumulating evidence indicates that galectin-3 may also promote atherogenesis through inducing endothelial dysfunction. Lectin-like oxidized low-density lipoprotein (oxLDL) receptor-1 (LOX-1), a receptor for oxLDL uptake, contributes to oxLDL-induced endothelial dysfunction. Whether galectin-3 induces endothelial dysfunction through modulation of LOX-1-mediated signaling remains unclear. In the present study, we explored the mechanisms underlying galectin-3 enhanced cytotoxicity of oxLDL in human umbilical vein endothelial cells (HUVECs) and the role of LOX-1. Incubation of HUVECs with galectin-3 increased the expression of LOX-1 in RNA and protein levels. In addition, the expression of LOX-1 induced by oxLDL was promoted by galectin-3. However, pretreatment of LOX-1 antibody reduced LOX-1 mRNA expression level in cells with oxLDL plus galectin-3 incubation. Compared to cells treated with oxLDL alone, reactive oxygen species (ROS) generation via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and subsequent activation of p38 mitogen-activated protein kinases followed by nuclear factor kappa B (NF-κB) activation and related inflammatory responses including adhesion molecule expression, adhesiveness of monocytic cells, and IL-8 release were also aggravated in cells treated with galectin-3 combined with oxLDL. Compared to cells treated with galectin-3 plus oxLDL group. We found that LOX-1 antibody mitigated NADPH oxidase activity, p-38 up-regulation, NF-κB activation, and proinflammatory responses in cells treated with galectin-3 combined with oxLDL. We conclude that galectin-3 enhances endothelial LOX-1 expression and propose a new mechanism by which galectin-3 may promote endothelial dysfunction by inducing inflammation via LOX-1/ROS/p38/NF-κB-mediated signaling pathway.
半乳糖凝集素-3（Galectin-3）是一种连接氧化应激和炎症的生物标志物，参与动脉粥样血栓形成的多种机制，如炎症、增殖或巨噬细胞趋化性。越来越多的证据表明，半乳糖凝集素-3 还可能通过诱导内皮功能障碍促进动脉粥样硬化形成。凝集素样氧化型低密度脂蛋白（oxLDL）受体-1（LOX-1）是 oxLDL 摄取的受体，有助于 oxLDL 诱导的内皮功能障碍。半乳糖凝集素-3 是否通过调节 LOX-1 介导的信号转导诱导内皮功能障碍尚不清楚。本研究探讨了半乳糖凝集素-3 增强人脐静脉内皮细胞（HUVEC）oxLDL 细胞毒性的机制以及 LOX-1 的作用。用半乳糖凝集素-3 孵育 HUVEC 可增加 RNA 和蛋白水平的 LOX-1 表达。此外，半乳糖凝集素-3 可促进 oxLDL 诱导的 LOX-1 表达。然而，用 LOX-1 抗体预处理可降低 oxLDL 加半乳糖凝集素-3 孵育细胞中 LOX-1mRNA 的表达水平。与单独用 oxLDL 处理的细胞相比，通过烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶激活产生的活性氧（ROS）生成以及随后的 p38 丝裂原激活蛋白激酶（p38 MAPK）激活和核因子κB（NF-κB）激活以及相关的炎症反应，包括粘附分子表达、单核细胞黏附性和 IL-8 释放，在用半乳糖凝集素-3 联合 oxLDL 处理的细胞中也加重。与用 galectin-3 加 oxLDL 处理的细胞相比。我们发现，LOX-1 抗体减轻了 galectin-3 联合 oxLDL 处理细胞中 NADPH 氧化酶活性、p38 上调、NF-κB 激活和促炎反应。我们得出结论，半乳糖凝集素-3 增强内皮 LOX-1 表达，并提出一种新的机制，即半乳糖凝集素-3 通过 LOX-1/ROS/p38/NF-κB 介导的信号通路诱导炎症来促进内皮功能障碍。
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