The Key Laboratory of Geriatrics, Beijing Hospital & Beijing Institute of Geriatrics, Ministry of Health, Beijing, P. R. China ; Beijing University of Chinese Medicine, Beijing, P. R. China.
PLoS One. 2013 Sep 17;8(9):e74769. doi: 10.1371/journal.pone.0074769. eCollection 2013.
Oxidized low-density lipoprotein (ox-LDL) is an important risk factor in the development of atherosclerosis. LOX-1, a lectin-like receptor for ox-LDL, is present primarily on endothelial cells and upregulated by ox-LDL, tumor necrosis factor a, shear stress, and cytokines in atherosclerosis. Recent studies demonstrated that ginkgolide B, a platelet-activating factor receptor antagonist, has antiinflammatory and antioxidant effects on endothelial and nerve cells. The present study investigated the effects of ginkgolide B on LOX-1 expression and the possible mechanism of action. Our results showed that ginkgolide B inhibited LOX-1 and intercellular cell adhesion molecule-1 (ICAM-1) expression in ox-LDL-stimulated endothelial cells through a mechanism associated with the attenuation of Akt activation. Similar data were obtained by silencing Akt and LY294002. We also evaluated Sirt1 and nuclear factor erythroid 2-related factor 2 (Nrf2) expression. These molecules play a protective role in endothelial cell injury. The results showed that ginkgolide B increased Sirt1 expression in ox-LDL-treated cells. The inhibitory effects of ginkgolide B on LOX-1 and ICAM-1 expression were reduced in Sirt1 siRNA-transfected cells. Nrf2 expression was increased in ox-LDL-treated cells, and ginkgolide B downregulated Nrf2 expression. These results suggest that ginkgolide B reduces Nrf2 expression by inhibiting LOX-1 expression, consequently reducing oxidative stress injury in ox-LDL-stimulated cells. Altogether, these results indicate that the protective effect of ginkgolide B on endothelial cells may be attributable to a decrease in LOX-1 expression and an increase in Sirt1 expression in ox-LDL-stimulated endothelial cells, the mechanism of which is linked to the inhibition of Akt activation. Ginkgolide B may be a multiple-target drug that exerts protective effects in ox-LDL-treated human umbilical vein endothelial cells.
氧化型低密度脂蛋白（ox-LDL）是动脉粥样硬化发展的重要危险因素。LOX-1 是 ox-LDL 的凝集素样受体，主要存在于内皮细胞中，并可被 ox-LDL、肿瘤坏死因子 a、切应力和细胞因子等在动脉粥样硬化中上调。最近的研究表明，血小板激活因子受体拮抗剂银杏内酯 B 对内皮细胞和神经细胞具有抗炎和抗氧化作用。本研究探讨了银杏内酯 B 对 LOX-1 表达的影响及其可能的作用机制。我们的结果表明，银杏内酯 B 通过与 Akt 激活减弱相关的机制抑制 ox-LDL 刺激的内皮细胞中 LOX-1 和细胞间黏附分子-1（ICAM-1）的表达。通过沉默 Akt 和 LY294002 获得了类似的数据。我们还评估了 Sirt1 和核因子红细胞 2 相关因子 2（Nrf2）的表达。这些分子在内皮细胞损伤中起保护作用。结果表明，银杏内酯 B 增加了 ox-LDL 处理细胞中的 Sirt1 表达。在 Sirt1 siRNA 转染的细胞中，银杏内酯 B 对 LOX-1 和 ICAM-1 表达的抑制作用降低。Nrf2 的表达在 ox-LDL 处理的细胞中增加，而银杏内酯 B 下调了 Nrf2 的表达。这些结果表明，银杏内酯 B 通过抑制 LOX-1 表达降低 Nrf2 表达，从而减少 ox-LDL 刺激的细胞中的氧化应激损伤。总之，这些结果表明，银杏内酯 B 对内皮细胞的保护作用可能归因于 ox-LDL 刺激的内皮细胞中 LOX-1 表达的降低和 Sirt1 表达的增加，其机制与 Akt 激活的抑制有关。银杏内酯 B 可能是一种多靶点药物，在 ox-LDL 处理的人脐静脉内皮细胞中发挥保护作用。
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