神经酰胺在糖尿病血管内皮细胞功能紊乱中的机制研究

项目名称： 神经酰胺在糖尿病血管内皮细胞功能紊乱中的机制研究

项目编号： No.30871190

项目类型： 面上项目

立项/批准年度： 2009

项目学科： 化学工业

项目作者： 雷闽湘

作者单位： 中南大学

项目金额： 30万元

中文摘要： 糖尿病血管并发症是糖尿病致死致残的主要原因，目前发病机制未完全阐明。内皮细胞结构、功能紊乱是促进糖尿病血管病变发生发展的关键。内皮细胞功能紊乱的最初特点是NO生物活性的改变。神经酰胺是脂质第二信使，广泛参与了细胞信号通路的调节，已发现神经酰胺可在多个水平上阻断胰岛素信号转导的IRS-1/PI3K/PKB，血管内皮细胞是胰岛素靶组织，并存在着独特的胰岛素信号转导通路IRS-1/PI3K/PKB/eNOS，最终导致eNOS的活化及NO产生。神经酰胺是否影响内皮细胞功能目前尚无文献报道，我们的初步研究已发现高糖使内皮细胞神经酰胺产生增多导致内皮细胞凋亡增加，游离脂肪酸所致的血管内皮细胞功能紊乱与神经酰胺对血管内皮细胞信号通路的抑制有关。因此我们将进一步研究糖代谢紊乱状态神经酰胺与血管内皮细胞功能的关系，减少神经酰胺积聚能否改善内皮细胞功能。其目的是为糖尿病血管并发症的防治提供新的治疗靶点。

中文关键词： 神经酰胺；糖尿病； 血管内皮细胞 ；NO；信号通路

英文摘要： Although the precise underlying molecular mechanisms are not fully elucidated, diabetic vascular complications may be important contributors to the increased mortality of diabetes. Endothelium plays multiple roles in the cardiovascular functions. Ceramide, one of the most important second messenger, blocks insulin signaling pathway IRS-1/PI3K/PKB at multiple levels. In the vasculature, insulin enhances the activation and expression of endothelial nitric oxide synthase (eNOS), which leads to the increase of nitric oxide (NO) to exert wide array of antiatherogenic actions16,17. Since Akt/protein kinase B, a serine/threonine kinase, is known to mediate insulin-induced phosphorylation of eNOS at Ser1177 that is responsible for the increased eNOS activity and NO production. The effect of accumulation of ceramide on endothelial dysfunction was not extensively studied before.Our study shows that high glucose resulted in a significant increase in the endothelial apoptosis through ceramide accumulation. FFAs inhibited eNOS activity through ceramide accumulation, which may promote onset of endothelial dysfunction. We will further demonstrated whether ceramide-mediated glucose actions on the development of endothelial dysfunction and atherosclerosis in diabetes and provide an new target for endothelial dysfunction.

英文关键词： Ceramide；Diabetes； Endothelium； NO；Signaling Pathway