title: Vildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressing advanced glycation end product-receptor axis.
abstract: Vildagliptin is a stable inhibitor of dipeptidyl peptidase-IV, a responsible enzyme that mainly inactivates glucagon-like peptide-1, and now one of the widely used agents for the treatment of diabetes. However, effects of vildagliptin on vascular injury in diabetes are largely unknown. Since advanced glycation end products (AGEs) and their receptor RAGE axis are reported to contribute to vascular complications in diabetes, we investigated here whether vildagliptin inhibits vascular damage in thoracic aorta of Otsuka Long-Evans Tokushima Fatty rats (OLETF rats), an animal model of type 2 diabetes with obesity, by blocking the AGEs-RAGE axis. OLETF and control LETO rats at 22 weeks old were given vehicle or 3 mg/kg of vildagliptin for another 12 weeks. Vildagliptin treatment decreased fasting plasma glucose and heart rate in OLETF rats. Compared with control LETO rats, levels of AGEs, RAGE mRNA and protein, an oxidative stress marker, 8-hydroxydeoxyguanosine, two membrane components of NADPH oxidase, p22 and gp91phox mRNAs, and phospho-NF-κB p65 in thoracic aorta were significantly enhanced in OLETF rats, all of which were inhibited by the treatment with vildagliptin. Vildagliptin significantly reduced both mRNA and protein levels of monocyte chemoattractant protein-1, vascular cell adhesion molecule-1 and plasminogen activator inhibitor-1 in thoracic aorta of OLETF rats. Enhanced expression of transforming growth factor-β in the aorta of diabetic rats was also suppressed by vildagliptin. Our present data suggest that vildagliptin could play a protective role against vascular injury in diabetes partly by attenuating the deleterious effects of AGEs-RAGE-oxidative stress axis.
authors.affiliation: Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume 830-0011, Fukuoka, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Matsui
authors.forename: Yuri
authors.initials: Y
authors.lastname: Nishino
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Sho-ichi
authors.initials: S
authors.lastname: Yamagishi
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D008297:Male; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use*; D009765:Obesity / Q000150:complications; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D020334:Rats, Inbred OLETF; D057772:Vascular System Injuries / Q000188:drug therapy* / Q000473:pathology; D000077597:Vildagliptin
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D017127:Glycation End Products, Advanced; D009570:Nitriles; D011759:Pyrrolidines; D000077597:Vildagliptin; D000218:Adamantane