RNA氧化在高糖诱导血管内皮功能障碍的作用机制研究

The vascular complications of diabetes mellitus(DM) impose a huge burden on the management of this disease because they often lead to disability and death. Hyperglycemia-induced oxidative stress is associated with vascular endothelial dysfunction and it is the essential pathogenesis of vascular disease in DM.It is recent years found that RNA oxidation is a novel pathogenic mechanism. Researchers have demonstrated that the RNA oxidation marker 8-oxo-7,8-dihydroguanosine(8-oxoG) is an independent predictor of mortality in patients with DM. It is the first evidence that RNA oxidation is correlated to diabetic complications. Our previous results show that urinary excretion of 8-oxoG is an important biomarker for oxidative stress in mammals. Most importantly, our results also indicate that urine 8-oxoG is increased significantly in diabetic rats. Therefore, we suppose that hyperglycemia-induced oxidative stress may lead to increased RNA oxidation in vascular endothelial cells, which may be the initiating factor for endothelial dysfunction. In order to confirm this hypothesis, we intend to investigate the correlation between hyperglycemia and RNA oxidation in vascular endothelial cells and different organs of diabetic rats. In addition, we want to prove the relationship between increased RNA oxidation and vascular endothelial dysfunction in human umbilical vein endothelial cells and brain microvascular endothelial cells. Finally, we will reveal the possible role of RNA oxidation involved in hyperglycemia-induced vascular endothelial dysfunction.

糖尿病血管并发症是糖尿病致死或致残的主要原因。高糖诱导血管内皮细胞的氧化应激引起血管内皮功能障碍是糖尿病血管并发症的病理基础；最近研究提示RNA氧化是新的致病机制，有学者发现尿中的RNA氧化标志物8-oxoG是糖尿病死亡的独立预测指标，首次将RNA氧化与糖尿病并发症相关联。我们的研究显示尿中的8-oxoG是哺乳动物氧化应激的敏感指标，糖尿病模型鼠的尿中8-oxoG显著增高。据此，我们提出高糖引起内皮细胞的高度氧化应激可导致RNA氧化增加，RNA氧化增加可能是血管内皮功能障碍启动因素的假设。本研究我们拟用糖尿病模型鼠研究高糖与血管内皮细胞RNA氧化的相关性，高糖与糖尿病模型鼠各脏器RNA氧化的相关性，RNA氧化与血管病变间的相关性；拟用人脑微血管内皮细胞和人脐静脉内皮细胞证明RNA氧化增加与血管内皮功能障碍的相关性，为揭示高糖诱导的血管内皮功能障碍中RNA氧化的作用机制提供科学的实验依据。

糖尿病血管并发症是糖尿病致死或致残的主要原因。RNA氧化损伤是一种新发现的致病机制。为了探讨高糖诱导的血管内皮功能障碍中RNA氧化的作用机制，本研究以链脲佐菌素（STZ）诱导建立了糖尿病大鼠模型，运用敏感精确的同位素稀释高效液相-串联质谱（ID-LC-MS/MS）方法，探索了高糖与糖尿病模型鼠各脏器RNA氧化的相关性；并进一步探讨了RNA氧化与血管病变间的相关性，以及RNA氧化损伤与糖尿病肾病发生发展的关系。本研究结果显示高糖引起的氧化应激增强可以造成小鼠模型多脏器核酸氧化损伤增加；而且不同脏器对高糖引起的核酸氧化损伤的易感性不同，以高糖状态下肾脏核酸氧化损伤最为显著。本研究结果还表明，随着高糖血症的持续RNA氧化损伤出现更早且更为广泛，RNA氧化损伤的出现早于糖尿病肾病且与肾损伤关系密切。根据本研究结果，我们认为尿液中的8-oxo-Gsn可以作为糖尿病及糖尿病肾病氧化应激状态的良好指标。本研究不仅为RNA氧化增加与血管内皮功能障碍的相关性研究提供了科学的实验依据，同时也发现了良好的糖尿病及糖尿病肾病评估预测指标。