title: Advanced glycation end products-induced reactive oxygen species generation is partly through NF-kappa B activation in human aortic endothelial cells.
abstract: Tumor necrosis factor (TNF)-α and reactive oxygen species (ROS) are involved in the endothelial dysfunction and the progression of atherosclerosis. In the pathogenesis of diabetic micro- and macro-vascular complications, advanced glycation end products (AGEs) and their receptor signaling are thought to play pivotal roles. We have studied the interaction among AGEs, TNF-α and ROS production using human aortic endothelial cells (HAoEC), and elucidated the significance of transcription factor NF-κB in that interaction. Concentration of TNF-α as well as 8-hydroxy-2'-deoxyguanosine (8-OHdG), an indicator of ROS generation, in the culture medium was significantly elevated 24 h after treatment with glycolaldehyde-derived AGE3. Antioxidant TEMPOL almost completely inhibited AGE3-induced TNF-α secretion, whereas NF-κB inhibitor PDTC partly suppressed AGE3-induced 8-OHdG production. Since NF-κB, which induces TNF-α expression is activated by ROS and TNF-α itself, AGE3-induced ROS generation is partly through NF-κB activation and subsequent TNF-α production in these cells. Our findings suggest that sustained activation of NF-κB might be crucial for endothelial dysfunction in diabetes, and that inhibition of local NF-κB and/or TNF-α action could be one of therapeutic strategies for vascular complications.
authors.affiliation: Department of Internal Medicine 1, Shimane University Faculty of Medicine, Shimane, Japan.
authors.forename: Miwa
authors.initials: M
authors.lastname: Morita
authors.forename: Shozo
authors.initials: S
authors.lastname: Yano
authors.forename: Toru
authors.initials: T
authors.lastname: Yamaguchi
authors.forename: Toshitsugu
authors.initials: T
authors.lastname: Sugimoto
mesh_terms: D000447:Aldehydes / Q000494:pharmacology; D001011:Aorta / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000447:Aldehydes; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D014409:Tumor Necrosis Factor-alpha