title: A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice.
abstract: OBJECTIVE
  The main pathophysiology of abdominal aortic aneurysm (AAA) considerably overlaps with that of atherosclerosis. We reported that incretins [glucagon-like peptide (GLP)-1 and glucose-dependent insulinotropic polypeptide (GIP)] or a dipeptidyl peptidase-4 inhibitor (DPP-4I) suppressed atherosclerosis in apolipoprotein E-null (Apoe－/－) mice. Here we investigated the effects of incretin-related agents on AAA in a mouse model.
  
  
  METHODS
  Apoe－/－ mice maintained on an atherogenic diet were subcutaneously infused with saline, Ang II (2000 ng/kg/min), Ang II, and native GLP-1 (2.16 nmol/kg/day) or Ang II and native GIP (25 nmol/kg/day) for 4 weeks. DPP-4I (MK0626, 6 mg/kg/day) was provided in the diet to the Ang II-infused mice with or without incretin receptor antagonists [(Pro3) GIP and exendin (9-39)].
  
  
  RESULTS
  AAA occurred in 70% of the animals receiving Ang II. DPP-4I reduced this rate to 40% and significantly suppressed AAA dilatation, fibrosis, and thrombosis. In contrast, incretins failed to attenuate AAA. Incretin receptor blockers did not reverse the suppressive effects of DPP-4I on AAA. In the aorta, DPP-4I significantly reduced the expression of Interleukin-1β and increased that of tissue inhibitor of metalloproteinase (TIMP)-2. In addition, DPP-4I increased the ratio of TIMP-2 to matrix metalloproteinases-9.
  
  
  CONCLUSIONS
  DPP-4I, MK0626, but not native incretins has protective effects against AAA in Ang II-infused Apoe－/－ mice via suppression of inflammation, proteolysis, and fibrosis in the aortic wall.
authors.affiliation: Department of Medicine, Division of Diabetes, Metabolism, and Endocrinology, Showa University School of Medicine.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kohashi
authors.forename: Munenori
authors.initials: M
authors.lastname: Hiromura
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Mori
authors.forename: Michishige
authors.initials: M
authors.lastname: Terasaki
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Hideki
authors.initials: H
authors.lastname: Kushima
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinmura
authors.forename: Masako
authors.initials: M
authors.lastname: Tomoyasu
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nagashima
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Hirano
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001011:Aorta / Q000473:pathology; D017544:Aortic Aneurysm, Abdominal / Q000188:drug therapy*; D001057:Apolipoproteins E / Q000235:genetics; D001794:Blood Pressure; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D005749:Gastric Inhibitory Polypeptide / Q000494:pharmacology; D005786:Gene Expression Regulation; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D054795:Incretins / Q000494:pharmacology*; D007249:Inflammation; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000473:pathology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; C587672:IL1B protein, mouse; D054795:Incretins; D053583:Interleukin-1beta; D000804:Angiotensin II; D019716:Tissue Inhibitor of Metalloproteinase-2; D005749:Gastric Inhibitory Polypeptide; D052216:Glucagon-Like Peptide 1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse