Dragomir Elena, Tircol Magdalena, Manduteanu Ileana, Voinea Manuela, Simionescu Maya
Institute of Cellular Biology and Pathology Nicolae Simionescu, Bucharest, 8, BP Hasdeu Street, PO Box 35-14, 79691-Bucharest, Romania.
Vascul Pharmacol. 2006 Jun;44(6):440-9. doi: 10.1016/j.vph.2006.02.006. Epub 2006 Apr 5.
Activated endothelial cells express monocyte chemoattractant protein-1 (MCP-1), a chemokine which is reportedly involved in the recruitment of plasma monocytes in the early stages of atherosclerosis. Since accelerated atherosclerosis is the main complication of diabetes and both diseases encompass an inflammatory reaction, we hypothesized that the anti-inflammatory drugs, aspirin and peroxisome proliferator-activated receptor (PPAR-alpha) activators (fenofibrate and clofibrate), could have an effect on the high glucose-induced MCP-1 expression in endothelial cells. To test this assumption, as well as the possible mechanisms involved, the MCP-1 expression and secretion, the reactive oxygen species levels, nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) expression were determined in human endothelial cells exposed to high glucose concentrations in the presence of aspirin, fenofibrate and clofibrate. Human endothelial cells kept in normal glucose concentration in the absence of drugs were used as control. The results showed that (i) aspirin, fenofibrate and clofibrate decrease significantly the MCP-1 expression and secretion in human endothelial cells; (ii) the high glucose up-regulated expression of MCP-1 in endothelial cells was significantly reduced by inhibitors of NF-kB and reactive oxygen species; (iii) all drugs notably decrease the level of the reactive oxygen species and activation of NF-kB and AP-1. Together, the findings indicate that in endothelial cells aspirin and PPAR-alpha activators reduce the high glucose-increased expression of MCP-1 by a mechanism that includes the inhibition of reactive oxygen species, and decrease of AP-1 and NF-kB activation.
活化的内皮细胞表达单核细胞趋化蛋白-1（MCP-1），据报道这种趋化因子参与动脉粥样硬化早期血浆单核细胞的募集。由于动脉粥样硬化加速是糖尿病的主要并发症，且这两种疾病都包含炎症反应，我们推测抗炎药物阿司匹林和过氧化物酶体增殖物激活受体（PPAR-α）激活剂（非诺贝特和氯贝丁酯）可能会对高糖诱导的内皮细胞中MCP-1的表达产生影响。为了验证这一假设以及其中可能涉及的机制，我们测定了在阿司匹林、非诺贝特和氯贝丁酯存在的情况下，暴露于高糖浓度的人内皮细胞中MCP-1的表达和分泌、活性氧水平、核因子-κB（NF-κB）和激活蛋白-1（AP-1）的表达。将未使用药物且保持在正常葡萄糖浓度的人内皮细胞用作对照。结果表明：（i）阿司匹林、非诺贝特和氯贝丁酯显著降低人内皮细胞中MCP-1的表达和分泌；（ii）NF-κB和活性氧抑制剂可显著降低高糖上调的内皮细胞中MCP-1的表达；（iii）所有药物均显著降低活性氧水平以及NF-κB和AP-1的激活。总之，这些发现表明在内皮细胞中，阿司匹林和PPAR-α激活剂通过包括抑制活性氧、降低AP-1和NF-κB激活在内的机制，减少高糖增加的MCP-1表达。
