Zhang Y, Shi H, Sun G, Li S, Xu X, Ye C, Li X, Wang S
Vascular Surgery Institute, Department of Vascular Surgery, First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Exp Clin Endocrinol Diabetes. 2011 Apr;119(4):225-33. doi: 10.1055/s-0030-1255054. Epub 2010 Jul 12.
Oxidative stress and inflammation are involved in the pathogenesis of diabetic endothelial dysfunction. Herein we reported the biological changes induced by hyperglycemia in human umbilical vein endothelial cells (HUVECs) and the potential underlying mechanisms sought to determine whether high glucose concentration or the persistence plays a key role in the development of vascular lesions. The HUVECs were exposed to various glucose concentrations (5, 15, 30, and 60 mmol/L of D-glucose supplemented), and several oxidative stress factors, such as NO, NOS, and ROS, and inflammatory signaling markers, such as TNF-α, TNFR, RIP, TRADD, TRAF-2 and NF-κB, were analyzed at various times (24, 48, 72, and 96 h). High glucose (HG) induced a transient increase of NO within 24 h and decreased afterwards, in accord with the expression of eNOS. HG also increased ROS and TNF-α production and activated the TNF-α-mediated signal transduction, decreasing cell viability and inducing apoptosis. However, 3 HG groups had similar effects on HUVECs with the increased duration of exposure, which resulted in the amplified oxidative and inflammatory damage. Taken together, these findings suggest that the HG persistence exacerbates oxidative stress and activates the inflammatory-mediated signaling pathways, inducing endothelial dysfunction and apoptosis, regardless of the concentration of HG. Our results provide the first evidence that HG persistence is more important than concentration in the progress of diabetic endothelial dysfunction.
氧化应激和炎症参与糖尿病性内皮功能障碍的发病机制。在此，我们报告了高血糖在人脐静脉内皮细胞（HUVECs）中诱导的生物学变化以及潜在的机制，试图确定高葡萄糖浓度或持续时间是否在血管病变发展中起关键作用。将HUVECs暴露于不同葡萄糖浓度（补充5、15、30和60 mmol/L的D-葡萄糖）下，并在不同时间点（24、48、72和96小时）分析几种氧化应激因子，如一氧化氮（NO）、一氧化氮合酶（NOS）和活性氧（ROS），以及炎症信号标志物，如肿瘤坏死因子-α（TNF-α）、肿瘤坏死因子受体（TNFR）、受体相互作用蛋白（RIP）、肿瘤坏死因子受体相关死亡结构域蛋白（TRADD）、肿瘤坏死因子受体相关因子2（TRAF-2）和核因子κB（NF-κB）。高糖（HG）在24小时内诱导NO短暂增加，随后下降，这与内皮型一氧化氮合酶（eNOS）的表达一致。HG还增加了ROS和TNF-α的产生，并激活了TNF-α介导的信号转导，降低细胞活力并诱导细胞凋亡。然而，3个HG组对HUVECs的影响相似，随着暴露时间的延长，导致氧化和炎症损伤加剧。综上所述，这些发现表明，无论HG浓度如何，HG的持续存在都会加剧氧化应激并激活炎症介导的信号通路，诱导内皮功能障碍和细胞凋亡。我们的结果提供了首个证据，即在糖尿病性内皮功能障碍的进展中，HG的持续存在比浓度更重要。
