Murao Koji, Yu Xiao, Cao Wen M, Imachi Hitomi, Chen Ke, Muraoka Tomie, Kitanaka Noriko, Li Junhun, Ahmed Rania A M, Matsumoto Kensuke, Nishiuchi Takamasa, Tokuda Masaaki, Ishida Toshihiko
Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
Life Sci. 2007 Jul 26;81(7):592-9. doi: 10.1016/j.lfs.2007.06.019. Epub 2007 Jul 3.
Monocyte chemoattractant protein-1 (MCP-1) is a 76-amino-acid chemokine thought to be the major chemotactic factor for monocytes. MCP-1 is found in macrophage-rich areas of atherosclerotic lesions. Recent report indicates that MCP-1 is induced by glucose-stimulation, raising the important link between diabetes mellitus and atherosclerosis. One of the rare sugars, d-psicose (d-ribo-2-hexulose) is present in small quantities in commercial carbohydrate complexes, however the physiological functions of d-psicose have not been evaluated. In this study, we examined the effects of d-psicose on MCP-1 expression in human umbilical vein endothelial cells (HUVECs). Results showed that MCP-1 mRNA and protein were stimulated following exposure to 22.4 mM glucose. Transcriptional activity of MCP-1 promoter paralleled endogenous expression of the gene and this activity was dependent on the dose of d-glucose. d-Psicose inhibited these effects. Next we used inhibitors of selected signal transduction pathways to show that high-glucose (HG) stimulated MCP-1 promoter activity was sensitive to p38-Mitogen-Activated Protein Kinase (p38-MAPK) pathway inhibitor. As expected, a dominant-negative p38-MAPK abolished the stimulatory effect of HG on the promoter activity. To incubate the cells with HG and d-psicose reduced the activation of p38-MAPK. Together, these results indicate that the d-psicose suppression of HG induced MCP-1 expression is mediated in part by inhibition of the p38-MAPK pathway and raise the possibility that d-psicose may be of therapeutic value in the treatment of diseases such as atherosclerosis.
单核细胞趋化蛋白-1（MCP-1）是一种由76个氨基酸组成的趋化因子，被认为是单核细胞的主要趋化因子。MCP-1存在于动脉粥样硬化病变中富含巨噬细胞的区域。最近的报告表明，MCP-1由葡萄糖刺激诱导产生，这揭示了糖尿病与动脉粥样硬化之间的重要联系。稀有糖之一的d-阿洛酮糖（d-核糖-2-己酮糖）在商业碳水化合物复合物中含量很少，然而其生理功能尚未得到评估。在本研究中，我们检测了d-阿洛酮糖对人脐静脉内皮细胞（HUVECs）中MCP-1表达的影响。结果显示，暴露于22.4 mM葡萄糖后，MCP-1的mRNA和蛋白表达均受到刺激。MCP-1启动子的转录活性与该基因的内源性表达平行，且这种活性依赖于d-葡萄糖的剂量。d-阿洛酮糖可抑制这些作用。接下来，我们使用了特定信号转导通路的抑制剂，结果表明高糖（HG）刺激的MCP-1启动子活性对p38丝裂原活化蛋白激酶（p38-MAPK）通路抑制剂敏感。正如预期的那样，显性负性p38-MAPK消除了HG对启动子活性的刺激作用。用HG和d-阿洛酮糖共同孵育细胞可降低p38-MAPK的激活。综上所述，这些结果表明d-阿洛酮糖对HG诱导的MCP-1表达的抑制作用部分是通过抑制p38-MAPK通路介导的，这也增加了d-阿洛酮糖在治疗动脉粥样硬化等疾病中具有治疗价值的可能性。
