白藜芦醇干预TLR4信号抑制糖化低密度脂蛋白所致血管内皮损伤的研究

Glycated low density lipoprotein (Gly-LDL) is increased in the body under the action of hyperglycemia indiabetic patients, which could cause the vascular endothelial injury. And the severity of diabetic vascular disease was positive related to the expression of Toll like receptor 4 (TLR4) gene. The Resveratrol, a natural antioxidant drug,has the pharmacologic action in anti-atherosclerosis. The preliminary study found that Gly-LDL could inhibit the proliferation and migration of vascular endothelial cells. Analysis of gene expression profiles also suggests that the Gly-LDL could lead to the activation of TLR4 gene in vascular endothelial cells, and Resveratrol can inhibit Gly-LDL induced vascular endothelial injury and activation of TLR4. Therefore, it was speculated that resveratrol maybe reduce the secretion of inflammatory factors by reducing the activity of TLR4 signal, thus reducing the vascular endothelial injury induced by Gly-LDL. This project is intended to discuss the effects of Gly-LDL on vascular endothelial cells and the mechanism of Resveratrol impact on the expression of TLR4 signaling pathway to inhibit vascular endothelial injury induced by Gly-LDL in vitro and in vivo, and provide new targets and scientific evidence for the treatment of diabetic vascular disease.

糖尿病患者高血糖下体内糖化低密度脂蛋白(Gly-LDL)增加，引起血管内皮损伤。而且糖尿病血管内皮损伤的严重程度与Toll样受体4(TLR4)的基因表达正相关，天然抗氧化药物白藜芦醇有抗动脉粥样硬化的药理作用。本项目前期发现Gly-LDL可抑制血管内皮细胞的增殖及迁移，数字基因表达谱分析提示Gly-LDL可引起血管内皮细胞TLR4信号的激活，而白藜芦醇可抑制Gly-LDL所引起的血管内皮损伤和TLR4的激活。由此推测白藜芦醇可能通过下调TLR4信号的活性，减少相关炎性因子的分泌，从而减轻Gly-LDL所导致的血管内皮损伤。本项目拟通过体内、外实验研究Gly-LDL对血管内皮细胞的损伤及白藜芦醇干预TLR4信号以抑制Gly-LDL所引起的血管内皮损伤，为糖尿病血管病变的治疗提供新的靶点及科学依据。

糖尿病患者高血糖下体内糖化低密度脂蛋白(Gly-LDL)增加，引起血管内皮损伤。而且糖尿病血管内皮损伤的严重程度与Toll样受体4(TLR4)的基因表达正相关，天然抗氧化药物白藜芦醇有抗动脉粥样硬化的药理作用。本项目发现Gly-LDL可抑制血管内皮细胞的增殖及迁移，数字基因表达谱分析提示Gly-LDL可引起血管内皮细胞TLR4信号的激活，而白藜芦醇可抑制Gly-LDL所引起的血管内皮损伤和TLR4的激活。进一步研究明确白藜芦醇可能通过下调TLR4信号的活性，减少相关炎性因子的分泌，从而减轻Gly-LDL所导致的血管内皮损伤。本项目通过体外实验，揭示了Gly-LDL诱导内皮细胞功能（增殖、迁移）下降，炎症标志物升高，通过沉默和过表达实验验证Gly-LDL调控内皮细胞中TLR4和HIF-1α的表达；而白藜芦醇可以改善这些变化。进一步的机制研究发现白藜芦醇可以通过调节炎性因子释放、抗氧化应激作用改善血管内皮细胞的增殖和迁移能力，白藜芦醇还能调控TLR4和HIF-1α，以及下游炎因子的释放。在体内实验中，我们进一步验证了白藜芦醇在糖尿病血管病变小鼠中的治疗作用，其机制与调控TLR4/HIF-1α介导的炎症通路相关，并且通过GST下拉实验发现TLR4和HIF-1α共同参与了糖尿病血管病变，为糖尿病血管病变的治疗提供了新的研究方向。综上所述，本项目通过体内、外实验研究Gly-LDL对血管内皮细胞的损伤及白藜芦醇干预TLR4信号以抑制Gly-LDL所引起的血管内皮损伤，为糖尿病血管病变的治疗提供新的靶点及科学依据。