title: Glucose-dependent insulinotropic polypeptide (GIP) inhibits signaling pathways of advanced glycation end products (AGEs) in endothelial cells via its antioxidative properties.
abstract: Glucose-dependent insulinotropic polypeptide (GIP) is one of the incretins, a gut hormone secreted from K cells in the intestine in response to food intake. It could be a potential therapeutic target for the treatment of patients with type 2 diabetes. However, effects of GIP on vascular injury remain unknown. Since interaction of advanced glycation end products (AGEs) with their receptor RAGE has been shown to play a crucial role in vascular damage in diabetes, this study investigated whether and how GIP blocked the deleterious effects of AGEs on human umbilical vein endothelial cells (HUVECs). GIP receptor was expressed in HUVECs. GIP, an analogue of cyclic AMP or inhibitors of NADPH oxidase inhibited the AGE-induced reactive oxygen species (ROS) generation in HUVECs. Furthermore, GIP reduced both RAGE mRNA and protein levels in HUVECs. GLP-1 also blocked the AGE-induced increase in mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and plasminogen activator inhibitor-1 in HUVECs. In addition, an antioxidant N-acetylcysteine mimicked the effects of GIP on RAGE and VCAM-1 gene expression in HUVECs. Our present study suggests that GIP could block the signal pathways of AGEs in HUVECs by reducing ROS generation and subsequent RAGE expression probably via GIP receptor-cyclic AMP axis.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Ojima
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: S
authors.initials: S
authors.lastname: Maeda
authors.forename: M
authors.initials: M
authors.lastname: Takeuchi
authors.forename: S
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D017127:Glycation End Products, Advanced / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D017127:Glycation End Products, Advanced; D017395:Plasminogen Activator Inhibitor 1; D017382:Reactive Oxygen Species; D000067759:Receptor for Advanced Glycation End Products; D011964:Receptors, Gastrointestinal Hormone; D011971:Receptors, Immunologic; D019010:Vascular Cell Adhesion Molecule-1; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor