title: Dipeptidyl peptidase-4 inhibition with linagliptin prevents western diet-induced vascular abnormalities in female mice.
abstract: BACKGROUND
  Vascular stiffening, a risk factor for cardiovascular disease, is accelerated, particularly in women with obesity and type 2 diabetes. Preclinical evidence suggests that dipeptidylpeptidase-4 (DPP-4) inhibitors may have cardiovascular benefits independent of glycemic lowering effects. Recent studies show that consumption of a western diet (WD) high in fat and simple sugars induces aortic stiffening in female C57BL/6J mice in advance of increasing blood pressure. The aims of this study were to determine whether administration of the DPP-4 inhibitor, linagliptin (LGT), prevents the development of aortic and endothelial stiffness induced by a WD in female mice.
  
  
  METHODS
  C56Bl6/J female mice were fed a WD for 4 months. Aortic stiffness and ex vivo endothelial stiffness were evaluated by Doppler pulse wave velocity (PWV) and atomic force microscopy (AFM), respectively. In addition, we examined aortic vasomotor responses and remodeling markers via immunohistochemistry. Results were analyzed via 2-way ANOVA, p < 0.05 was considered as statistically significant.
  
  
  RESULTS
  Compared to mice fed a control diet (CD), WD-fed mice exhibited a 24 % increase in aortic PWV, a five-fold increase in aortic endothelial stiffness, and impaired endothelium-dependent vasodilation. In aorta, these findings were accompanied by medial wall thickening, adventitial fibrosis, increased fibroblast growth factor 23 (FGF-23), decreased Klotho, enhanced oxidative stress, and endothelial cell ultrastructural changes, all of which were prevented with administration of LGT.
  
  
  CONCLUSIONS
  The present findings support the notion that DPP-4 plays a role in development of WD-induced aortic stiffening, vascular oxidative stress, endothelial dysfunction, and vascular remodeling. Whether, DPP-4 inhibition could be a therapeutic tool used to prevent the development of aortic stiffening and the associated cardiovascular complications in obese and diabetic females remains to be elucidated.
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA.
authors.forename: Camila
authors.initials: C
authors.lastname: Manrique
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA.
authors.forename: Javad
authors.initials: J
authors.lastname: Habibi
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA.
authors.forename: Annayya R
authors.initials: AR
authors.lastname: Aroor
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.|Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA.|The Dalton Cardiovascular Research Center, Columbia, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Sowers
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA.
authors.forename: Guanghong
authors.initials: G
authors.lastname: Jia
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.
authors.forename: Melvin R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Garro
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA.|The Dalton Cardiovascular Research Center, Columbia, USA.
authors.forename: Luis A
authors.initials: LA
authors.lastname: Martinez-Lemus
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA.|The Dalton Cardiovascular Research Center, Columbia, USA.
authors.forename: Francisco I
authors.initials: FI
authors.lastname: Ramirez-Perez
authors.affiliation: Boehringer Ingelheim Pharma, Ingelheim Am Rhein, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klein
authors.affiliation: Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA.|The Dalton Cardiovascular Research Center, Columbia, USA.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Meininger
authors.affiliation: Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, University of Missouri-Columbia School of Medicine, One Hospital Drive, Columbia, MO, 65212, USA. demarcov@missouri.edu.|MU Diabetes and Cardiovascular Research Center, University of Missouri, School of Medicine, Columbia, USA. demarcov@missouri.edu.|Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine, Columbia, USA. demarcov@missouri.edu.|Research Service, Harry S. Truman Memorial Veterans Hospital, Columbia, USA. demarcov@missouri.edu.|The Dalton Cardiovascular Research Center, Columbia, USA. demarcov@missouri.edu.
authors.forename: Vincent G
authors.initials: VG
authors.lastname: DeMarco
mesh_terms: D000818:Animals; D001011:Aorta / Q000187:drug effects; D066273:Diet, Western; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D000089703:Fibroblast Growth Factor-23; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000069476:Linagliptin / Q000494:pharmacology*; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications*; D063177:Pulse Wave Analysis; D066253:Vascular Remodeling / Q000187:drug effects / Q000502:physiology; D059289:Vascular Stiffness / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; C000717428:Fgf23 protein, mouse; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D000089703:Fibroblast Growth Factor-23
keywords: Atomic force microscopy; Pulse wave velocity