title: The dipeptidyl peptidase-4 inhibitor saxagliptin improves function of circulating pro-angiogenic cells from type 2 diabetic patients.
abstract: BACKGROUND
  Type 2 diabetes (T2D) is associated with reduction and dysfunction of circulating pro-angiogenic cells (PACs). DPP-4 inhibitors, a class of oral agents for T2D, might possess pleiotropic vasculoprotective activities. Herein, we tested whether DPP-4 inhibition with Saxagliptin affects the function of circulating PACs from T2D and healthy subjects.
  
  
  METHODS
  PACs were isolated from T2D (n = 20) and healthy (n = 20) subjects. Gene expression, clonogenesis, proliferation, adhesion, migration and tubulisation were assessed in vitro by incubating PACs with or without Saxagliptin and SDF-1α. Stimulation of angiogenesis by circulating cells from T2D patients treated with Saxagliptin or other non-incretinergic drugs was assessed in vivo using animal models.
  
  
  RESULTS
  Soluble DPP-4 activity was predominant over cellular activity and was successfully inhibited by Saxagliptin. At baseline, T2D compared to healthy PACs contained less acLDL(+)Lectin(+) cells, and showed altered expression of genes related to adhesion and cell cycle regulation. This was reflected by impaired adhesion and clonogenesis/proliferative response of T2D PACs. Saxagliptin + SDF-1α improved adhesion and tube sustaining capacity of PACs from T2D patients. CD14+ PACs were more responsive to Saxagliptin than CD14- PACs. While Saxagliptin modestly reduced angiogenesis by mature endothelial cells, circulating PACs-progeny cells from T2D patients on Saxagliptin treatment displayed higher growth factor-inducible in vivo angiogenetic activity, compared to cells from T2D patients on non-incretinergic regimen.
  
  
  CONCLUSIONS
  Saxagliptin reverses PACs dysfunction associated with T2D in vitro and improves inducible angiogenesis by circulating cells in vivo. These data add knowledge to the potential pleiotropic cardiovascular effects of DPP-4 inhibition.
authors.forename: Nicol
authors.initials: N
authors.lastname: Poncina
authors.forename: Mattia
authors.initials: M
authors.lastname: Albiero
authors.forename: Lisa
authors.initials: L
authors.lastname: Menegazzo
authors.forename: Roberta
authors.initials: R
authors.lastname: Cappellari
authors.forename: Angelo
authors.initials: A
authors.lastname: Avogaro
authors.affiliation: Venetian Institute of Molecular Medicine, University Hospital of Padova, Via Giustiniani, Padova 2, 35100, Italy. gianpaolo.fadini@unipd.it.
authors.forename: Gian Paolo
authors.initials: GP
authors.lastname: Fadini
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000175:diagnosis / Q000188:drug therapy*; D004151:Dipeptides / Q000494:pharmacology / Q000627:therapeutic use*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; C502994:saxagliptin; D000218:Adamantane