title: A dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin, improves endothelial function and reduces atherosclerotic lesion formation in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  The aim of this study was to investigate the antiatherogenic effects of the dipeptidyl peptidase-4 inhibitor, des-fluoro-sitagliptin (DFS).
  
  
  BACKGROUND
  The new class of anti-type 2 diabetes drugs, dipeptidyl peptidase-4 inhibitors, improves glucose metabolism by increasing levels of active glucagon-like peptide (GLP)-1.
  
  
  METHODS
  Endothelial function was examined by acetylcholine-induced endothelium-dependent vasorelaxation using aortic rings and atherosclerotic lesion development in the entire aorta in apolipoprotein E-deficient mice fed a high-fat diet with or without DFS, and the antiatherogenic effects of DFS were investigated in cultured human macrophages and endothelial cells. Plasma levels of active GLP-1 were measured in patients with or without coronary artery disease.
  
  
  RESULTS
  DFS significantly improved endothelial dysfunction (89.9 ± 3.9% vs. 79.2 ± 4.3% relaxation at 10(-4) mol/l acetylcholine, p < 0.05) associated with increased endothelial nitric oxide synthase phosphorylation and reduced atherosclerotic lesion area (17.7% [15.6% to 25.8%] vs. 24.6% [19.3% to 34.6%], p < 0.01) compared with vehicle treatment. In cultured human macrophages, DFS significantly increased GLP-1-induced cytosolic levels of cyclic adenosine monophosphate compared with GLP-1 alone, resulted in inhibiting phosphorylation of c-jun N-terminal kinase and extracellular signal-regulated kinase 1/2 and nuclear factor-kappa B p65 nuclear translocation through the cyclic adenosine monophosphate/protein kinase A pathway, and suppressed proinflammatory cytokines (i.e., interleukin-1-beta, interleukin-6, and tumor necrosis factor-alpha) and monocyte chemoattractant protein-1 production in response to lipopolysaccharide. DFS-enhanced GLP-1 activity sustained endothelial nitric oxide synthase phosphorylation and decreased endothelial senescence and apoptosis compared with GLP-1 alone. In the human study, fasting levels of active GLP-1 were significantly lower in patients with coronary artery disease than those without (3.10 pmol/l [2.40 to 3.62 pmol/l] vs. 4.00 pmol/l [3.10 to 5.90 pmol/l], p < 0.001).
  
  
  CONCLUSIONS
  A DPP-4 inhibitor, DFS, exhibited antiatherogenic effects through augmenting GLP-1 activity in macrophages and endothelium.
authors.affiliation: Department of Cardiovascular Medicine, Faculty of Life Sciences, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Matsubara
authors.forename: Seigo
authors.initials: S
authors.lastname: Sugiyama
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugamura
authors.forename: Taishi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Yukio
authors.initials: Y
authors.lastname: Fujiwara
authors.forename: Eiichi
authors.initials: E
authors.lastname: Akiyama
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kurokawa
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Nozaki
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ohba
authors.forename: Masaaki
authors.initials: M
authors.lastname: Konishi
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Maeda
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Izumiya
authors.forename: Koichi
authors.initials: K
authors.lastname: Kaikita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sumida
authors.forename: Hideaki
authors.initials: H
authors.lastname: Jinnouchi
authors.forename: Kunihiko
authors.initials: K
authors.lastname: Matsui
authors.forename: Shokei
authors.initials: S
authors.lastname: Kim-Mitsuyama
authors.forename: Motohiro
authors.initials: M
authors.lastname: Takeya
authors.forename: Hisao
authors.initials: H
authors.lastname: Ogawa
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011719:Pyrazines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D000068900:Sitagliptin Phosphate