白三烯B4在糖尿病诱导的内皮细胞功能障碍中的作用及其机制研究

As an important proinflammatory cytokine and chemokine, leukotriene B4 (LTB4) is significantly elevated in diabetes and atherosclerosis. The biological effects of LTB4 are mediated not only by BLT receptors, but also by peroxisome proliferator receptor α. However, the signal transduction pathways and the roles of the two types of the receptors seem to be not consistent, and the role of LTB4 in endothelial dysfunction in diabetes remains unclear. In this study, we intend to analyze the changes of LTB4 levels and the expression of its different receptor types in the streptozotocin (STZ)-induced diabetic rats, and observes the influence of different LTB4 receptors blockade on LTB4 levels, the expression of its different receptor types and endothelial cell function in both blood circulation and aorta. In the high glucose-induced injury model of human umbilical vein endothelial cells (HUVECs), we intend to observes the influences of LTB4 intervention and/or different LTB4 receptors blockade on LTB4 production, LTB4 receptor expression and endothelial cell function, in order to explore the roles of LTB4 on endothelial cell dysfunction in diabetes and its potential mechanism. The completion of this project will contribute to reveal new mechanisms involved in diabetic endothelial dysfunction, and will provide inspiration for the prevention and treatment of diabetic complications.

白三烯B4（LTB4）作为重要的致炎性细胞因子和趋化因子，其在糖尿病和动脉粥样硬化患者中均显著升高。LTB4发挥生物学效应既可由BLT受体介导，又可由过氧化物酶体增殖物激活受体α介导，但两类受体的信号转导和作用似乎并不一致，并且LTB4在糖尿病个体内皮细胞功能障碍中的作用尚不明确。本研究拟在链脲菌素（STZ）诱导糖尿病大鼠中分析LTB4水平及其不同受体类型表达的变化，观察阻断LTB4不同受体类型对血循环和动脉局部LTB4水平、LTB4受体表达及内皮细胞功能的影响。在体外培养的人脐静脉内皮细胞（HUVECs）的高糖损伤模型中，观察添加LTB4干预和（或）阻断LTB4不同类型受体对HUVECs的LTB4产生、LTB4受体表达及细胞功能的影响，探讨LTB4在糖尿病个体内皮细胞功能障碍中的作用及其潜在机制。本项目的完成将有助于揭示糖尿病个体发生内皮细胞功能障碍的新机制，为防治糖尿病并发症提供启示。

糖尿病是一种涉及慢性低度炎症的疾病。白三烯B4（LTB4）作为重要的致炎性细胞因子，在糖尿病和动脉粥样硬化患者中均显著升高，但其在糖尿病诱导的内皮细胞损伤及功能障碍中的作用尚不明确。LTB4发挥生物学效应可由BLT受体介导。我们的研究结果未观察到高糖培养的人脐静脉内皮细胞（HUVECs）中BLT1、BLT2受体表达水平的变化，提示糖尿病可能不是通过BLT受体诱导内皮细胞损伤。同时，我们的研究结果显示，一定浓度的LTB4干预会导致HUVECs内ROS水平的降低，提示在氧化应激方面，LTB4可能是一种保护因素，这一机制需要我们更深入的研究。