吴茱萸碱对嘌呤2X4受体介导糖尿病的慢性高葡萄糖和高脂肪酸引起血管内皮炎性损伤的作用及机理研究

Dysfunction and damage of the vessel endothelial cells induced by chronic hyperglycemia and hyperlipidemia is the principal cause for the cardiovascular diseases. The diabetic cardiovascular diseases involve oxidative stress and inflammatory factor release and protein kinase C activation and so on. The early symptoms of diabetic vascular diseases include the depression of endothelial dependent vasodilatation and the activation of the vessel endothelial inflamation. It is reported that P2X4 receptor of human umbilical vein endothelial cells is involved in inflammation, and its antagonist can lower the inflamation, dilate the blood vessels and lose weight, which suggest that P2X4 receptor is related with the pathogenesis of diabetic cardiovascular complication. Thus, the aim of the project is to observe the possible role and mechanism of P2X4 receptor in chronic hyperglycemia and hyperlipidemia to cause the damage of vessel endothelial cells. Furthermore, the project will determine whether evodiamine can protect the endothelial cells from damage through influencing P2X4 receptor specifically, and provide new experimental evidences for the prevention and treatment of diabetes and its cardiovascular complication.

慢性高血糖和并发的血脂障碍是导致糖尿病心血管并发疾病的主要因素。糖尿病心血管病变涉及氧化应激、炎性因子释放和蛋白激酶C激活等。血管内皮的功能失调和损伤在糖尿病心血管并发症的发病过程中具有关键作用。糖尿病所致血管病变的一个早期症状是内皮依赖性血管舒张反应的下降，同时引起血管的炎症反应。脐带血管内皮细胞P2X4受体参与炎性反应，研究显示吴茱萸碱有抗炎、扩张血管、减肥等作用，提示它可能影响P2X4受体介导慢性高葡萄糖和高脂肪酸引起的血管内皮炎性损伤病变，可能对糖尿病心血管并发症产生治疗作用。因此，本项目观察在长期高血糖和高脂肪酸的状态下P2X4受体对血管内皮细胞功能损伤产生的作用，以及从分子和细胞水平了解吴茱萸碱对P2X4受体介导血管内皮损伤作用的影响及可能机理，为探寻可能改善糖代谢的药物研究提供理论基础。

慢性高血糖和并发的血脂障碍是导致糖尿病心血管并发疾病的主要因素。血管内皮的功能失调和损伤在糖尿病心血管并发症的发病过程中具有关键作用。研究观察高血糖和高脂肪酸的状态下P2X4受体和其它炎性因子对血管内皮细胞功能产生的损伤及多种中药单体的保护作用。研究显示吴茱萸碱抑制高血糖和高脂肪酸的状态下人脐带内皮细胞P2X4受体上调表达，减少高糖诱导的细胞内活性氧（ROS）的浓度，降低血管内皮炎性损伤；大黄素降低高糖诱导人脐静脉内皮细胞凋亡，抑制高糖导致内皮细胞CCL5上调表达及粘附和趋化活性，对高糖诱导血管内皮细胞细胞毒性损害具有保护作用；柚皮苷减少CX3CL1的表达并改善线粒体功能，作为抗氧化剂对高糖损伤的人脐带内皮细胞起保护作用。本项目研究结果有助于从分子和细胞水平了解高糖高指对人脐带内皮细胞的损伤及可能机理，为探寻可能改善糖代谢的药物研究提供实验基础。