Department of Anatomy, College of Medicine, Yeungnam University, Daegu, South Korea.
Department of Pharmacology, College of Medicine, Yeungnam University, Daegu, South Korea.
J Cell Mol Med. 2017 Nov;21(11):2720-2731. doi: 10.1111/jcmm.13188. Epub 2017 Apr 26.
Methylglyoxal (MGO) is a reactive dicarbonyl metabolite of glucose, and its plasma levels are elevated in patients with diabetes. Studies have shown that MGO combines with the amino and sulphhydryl groups of proteins to form stable advanced glycation end products (AGEs), which are associated with vascular endothelial cell (EC) injury and may contribute to the progression of atherosclerosis. In this study, MGO induced apoptosis in a dose-dependent manner in HUVECs, which was attenuated by pre-treatment with z-VAD, a pan caspase inhibitor. Treatment with MGO increased ROS levels, followed by dose-dependent down-regulation of c-FLIP . In addition, pre-treatment with the ROS scavenger NAC prevented the MGO-induced down-regulation of p65 and c-FLIP , and the forced expression of c-FLIP attenuated MGO-mediated apoptosis. Furthermore, MGO-induced apoptotic cell death in endothelium isolated from mouse aortas. Finally, MGO was found to induce apoptosis by down-regulating p65 expression at both the transcriptional and posttranslational levels, and thus, to inhibit c-FLIP mRNA expression by suppressing NF-κB transcriptional activity. Collectively, this study showed that MGO-induced apoptosis is dependent on c-FLIP down-regulation via ROS-mediated down-regulation of p65 expression in endothelial cells.
甲基乙二醛（MGO）是葡萄糖的一种反应性二羰基代谢物，其在糖尿病患者中的血浆水平升高。研究表明，MGO 与蛋白质的氨基和巯基结合，形成稳定的晚期糖基化终产物（AGEs），这与血管内皮细胞（EC）损伤有关，并可能导致动脉粥样硬化的进展。在这项研究中，MGO 以剂量依赖性方式诱导 HUVEC 细胞凋亡，用广谱半胱天冬酶抑制剂 z-VAD 预处理可减弱这种诱导作用。用 MGO 处理会增加 ROS 水平，随后 c-FLIP 的表达呈剂量依赖性下调。此外，用 ROS 清除剂 NAC 预处理可防止 MGO 诱导的 p65 和 c-FLIP 下调，强制表达 c-FLIP 可减弱 MGO 介导的细胞凋亡。此外，MGO 可诱导从小鼠主动脉分离出的内皮细胞发生凋亡性细胞死亡。最后，研究发现 MGO 通过下调转录和翻译后水平的 p65 表达诱导细胞凋亡，从而通过抑制 NF-κB 转录活性抑制 c-FLIP mRNA 表达。总之，这项研究表明，MGO 诱导的细胞凋亡依赖于 c-FLIP 的下调，这是通过 ROS 介导的 p65 表达下调在内皮细胞中实现的。
