title: Dipeptidyl peptidase-4 inhibitor linagliptin attenuates neointima formation after vascular injury.
abstract: BACKGROUND
  Recently, glucagon-like peptide-1 (GLP-1)-based therapy, including dipeptidyl peptidase-4 (DPP-4) inhibitors and GLP-1 receptor agonists, has emerged as one of the most popular anti-diabetic therapies. Furthermore, GLP-1-based therapy has attracted increased attention not only for its glucose-lowering ability, but also for its potential as a tissue-protective therapy. In this study, we investigated the vascular-protective effect of the DPP-4 inhibitor, linagliptin, using vascular smooth muscle cells (VSMCs).
  
  
  METHODS
  Six-week-old male C57BL/6 mice were divided into control (n =19) and linagliptin (3 mg/kg/day, n =20) treated groups. Endothelial denudation injuries were induced in the femoral artery at 8 weeks of age, followed by evaluation of neointima formation at 12 weeks. To evaluate cell proliferation of rat aortic smooth muscle cells, a bromodeoxyuridine (BrdU) incorporation assay was performed.
  
  
  RESULTS
  Linagliptin treatment reduced vascular injury-induced neointima formation, compared with controls (p <0.05). In these non-diabetic mice, the body weight and blood glucose levels did not change after treatment with linagliptin. Linagliptin caused an approximately 1.5-fold increase in serum active GLP-1 concentration, compared with controls. In addition, the vascular injury-induced increase in the oxidative stress marker, urinary 8-OHdG, was attenuated by linagliptin treatment, though this attenuation was not statistically significant (p =0.064). Moreover, linagliptin did not change the serum stromal cell-derived factor-1α (SDF-1α) or the serum platelet-derived growth factor (PDGF) concentration. However, linagliptin significantly reduced in vitro VSMC proliferation.
  
  
  CONCLUSIONS
  Linagliptin attenuates neointima formation after vascular injury and VSMC proliferation beyond the glucose-lowering effect.
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. yuterawaki@yahoo.co.jp.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Terawaki
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. tnomiyama@fukuoka-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Nomiyama
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. namikawa9@fukuoka-u.ac.jp.
authors.forename: Takako
authors.initials: T
authors.lastname: Kawanami
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. yurikoh@fukuoka-u.ac.jp.
authors.forename: Yuriko
authors.initials: Y
authors.lastname: Hamaguchi
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. thebassistofmasterpiece@hotmail.co.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. tanakatomoko@fukuoka-u.ac.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tanaka
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. kunitakamura1121@yahoo.co.jp.
authors.forename: Kunitaka
authors.initials: K
authors.lastname: Murase
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. r_nagaishi@hotmail.com.
authors.forename: Ryoko
authors.initials: R
authors.lastname: Nagaishi
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. mtanabe@live.jp.
authors.forename: Makito
authors.initials: M
authors.lastname: Tanabe
authors.affiliation: Department of Endocrinology and Diabetes Mellitus, School of Medicine, Fukuoka University, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan. tyanase@fukuoka-u.ac.jp.
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Yanase
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D052216:Glucagon-Like Peptide 1 / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069476:Linagliptin; D008297:Male; D008810:Mice, Inbred C57BL; D058426:Neointima / Q000188:drug therapy*; D011687:Purines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D057772:Vascular System Injuries / Q000188:drug therapy*
chemical_list: D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011687:Purines; D011799:Quinazolines; D000069476:Linagliptin; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4