氧化苦参碱对A2B介导高糖高脂毒性下血管内皮细胞保护作用及机制研究

Diabetes mellitus has become an increasing epidemic metabolic disease, and it may trigger various kinds of cardiovascular complications which cause serious harm to human health. Dysfunction and damage of the vessel endothelial cells induced by chronic hyperglycemia and hyperlipidemia are the principal causes for the cardiovascular diseases. The early symptoms of diabetic vascular diseases include the depression of endothelial dependent vasodilatation and the activation of the inflammatory response in vessel endothelium. The diabetic cardiovascular diseases related to oxidative stress, inflammatory factor release and protein kinase C activation and so on. It is reported that A2B receptors may be involved in inflammation, and its antagonist can lower the blood lipid and glucose level, which suggest that A2B receptors are related with the pathogenesis of diabetic cardiovascular complication. Thus, the aim of the project is to observe the possible role and mechanism of A2B receptors in chronic hyperglycemia and hyperlipidemia to cause the damage of vessel endothelial cells. Furthermore, the project will also determine whether oxymatrine can protect the endothelial cells from diabetic damage through influencing A2B receptors specifically, which provide new experimental evidences for the prevention and treatment of diabetes and its cardiovascular complication.

糖尿病已成为发病率日益增加的流行性代谢疾病，由它引发的各种心血管病并发症对人类的身体健康造成严重的危害。慢性高血糖和高血脂引起的血管内皮功能失调和损伤是导致心血管疾病的主要原因。糖尿病所致血管病变的早期症状包括内皮依赖性血管舒张反应的下降和血管内皮炎症反应的激活。糖尿病心血管病变与氧化应激、炎症因子的释放以及蛋白激酶C的激活等有关。研究表明A2B受体涉及炎性作用，其拮抗剂有降血脂、降血糖作用，提示A2B受体涉及糖尿病心血管并发症的发病机理。因此，本项目观察A2B受体激活对在长期高血糖和高脂影响下血管内皮细胞所发生损伤的可能作用及其机理，以及氧化苦参碱是否可特异性作用于A2B受体对糖尿病血管内皮损伤产生保护效应，为糖尿病及其心血管并发病变的防治提供新实验基础。

糖尿病是由于胰岛素分泌绝对或相对不足引起的代谢性疾病，常伴有高血糖和高血脂症状。血管内皮细胞在糖尿病心血管并发症的发展中起着重要作用。慢性高血糖和高血脂引起的血管内皮功能失调和损伤是导致心血管疾病的主要原因。糖尿病所致血管病变的早期症状包括内皮依赖性血管舒张反应的下降和血管内皮炎症反应的激活。A2B 受体能在血管内皮细胞上表达，并对内皮细胞的功能可能起到调节作用。本项目观察了A2B受体激活对长期高血糖和高脂影响下血管内皮细胞所发生损伤的可能作用及其机理，以及氧化苦参碱（OMT）是否可特异性作用于A2B受体对糖尿病血管内皮损伤产生保护效应。结果表明高糖培养对人脐带静脉血管内皮细胞（HUVECs）具有一定毒性，高糖能够增加HUVECs的A2B受体表达，同时，氧化苦参碱能够抑制此增强作用。同源建模分子对接实验结果表明OMT与腺苷A2B受体有很好的结合位点。加入OMT对高糖毒性作用下的血管内皮细胞具有一定保护作用， 其机制可能和抑制细胞A2B受体的表达和炎性因子的释放，以及抑制p38和ERK1/2 MAPK信号通路磷酸化相关。