title: Minodronate, a nitrogen-containing bisphosphonate, inhibits advanced glycation end product-induced vascular cell adhesion molecule-1 expression in endothelial cells by suppressing reactive oxygen species generation.
abstract: Advanced glycation end products (AGEs), the senescent macroprotein derivatives that form in increased amounts in diabetes, have been implicated in the pathogenesis of diabetic vascular complications. Indeed, AGEs elicit oxidative stress generation in vascular wall cells through an interaction with their receptor (RAGE), thus playing an important role in vascular inflammation and altered gene expression of growth factors and cytokines. We have previously shown that minodronate, a nitrogen-containing bisphosphonate, blocked the angiogenic signaling of vascular endothelial growth factor in ECs through its antioxidative properties. However, the effects of minodronate on AGE-exposed ECs remain to be elucidated. In this study, we investigated whether and how minodronate could inhibit AGE-induced reactive oxygen species (ROS) generation and subsequent vascular cell adhesion molecule-1 (VCAM-1) gene expression in human umbilical vein endothelial cells (HUVEC). Minodronate or an NADPH oxidase inhibitor, diphenylene iodonium, completely inhibited the AGE-induced ROS generation in HUVEC. Geranylgeranyl pyrophosphate reversed the antioxidative properties of minodronate in AGE-exposed ECs. Furthermore, minodronate was found to prevent AGE-induced nuclear factor--KB activation and subsequently suppress VCAM-1 gene expression in HUVEC. These results demonstrate that minodronate could inhibit VCAM- 1 expression in AGE-exposed ECs by suppressing NADPH oxidase-derived ROS generation, probably via inhibition of geranylgeranylation of Rac, a component of endothelial NADPH oxidase. Our present study suggests that minodronate may have a therapeutic potential in the treatment of patients with diabetic vascular complications.
authors.affiliation: Department of Internal Medicine, Kurume University School of Medicine, Kurume, Japan. shoichi@med.kurume-u.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Yamagishi
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D002460:Cell Line; D004164:Diphosphonates / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D017127:Glycation End Products, Advanced / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors* / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000975:Antioxidants; D004164:Diphosphonates; D017127:Glycation End Products, Advanced; D007093:Imidazoles; D017382:Reactive Oxygen Species; D019010:Vascular Cell Adhesion Molecule-1; C087958:YM 529