title: Dipeptidyl peptidase-4 inhibitor decreases abdominal aortic aneurysm formation through GLP-1-dependent monocytic activity in mice.
abstract: Abdominal aortic aneurysm (AAA) is a life-threatening situation affecting almost 10% of elders. There has been no effective medication for AAA other than surgical intervention. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to have a protective effect on cardiovascular disease. Whether DPP-4 inhibitors may be beneficial in the treatment of AAA is unclear. We investigated the effects of DPP-4 inhibitor sitagliptin on the angiotensin II (Ang II)-infused AAA formation in apoE-deficient (apoE-/-) mice. Mice with induced AAA were treated with placebo or 2.5, 5 or 10 mg/kg/day sitagliptin. Ang II-infused apoE-/- mice exhibited a 55.6% incidence of AAA formation, but treatment with sitagliptin decreased AAA formation. Specifically, administered sitagliptin in Ang II-infused mice exhibited decreased expansion of the suprarenal aorta, reduced elastin lamina degradation of the aorta, and diminished vascular inflammation by macrophage infiltration. Treatment with sitagliptin decreased gelatinolytic activity and apoptotic cells in aorta tissues. Sitaglipitn, additionally, was associated with increased levels of plasma active glucagon-like peptide-1 (GLP-1). In vitro studies, GLP-1 decreased reactive oxygen species (ROS) production, cell migration, and MMP-2 as well as MMP-9 activity in Ang II-stimulated monocytic cells. The results conclude that oral administration of sitagliptin can prevent abdominal aortic aneurysm formation in Ang II-infused apoE-/-mice, at least in part, by increasing of GLP-1 activity, decreasing MMP-2 and MMP-9 production from macrophage infiltration. The results indicate that sitagliptin may have therapeutic potential in preventing the development of AAA.
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Hsin Ying
authors: HY
authors: Lu
authors: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Chun Yao
authors: CY
authors: Huang
authors: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Chun Ming
authors: CM
authors: Shih
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.
authors: Wei Hung
authors: WH
authors: Chang
authors: Division of Cardiovascular Surgery, Tri-Service General Hospital, Taipei, Taiwan.
authors: Chein Sung
authors: CS
authors: Tsai
authors: Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, Taiwan.
authors: Feng Yen
authors: FY
authors: Lin
authors: Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Cardiovascular Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors: Chun Che
authors: CC
authors: Shih
mesh_terms: D000804:Angiotensin II / Q000633:toxicity; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency; D017209:Apoptosis; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000166:cytology; D052216:Glucagon-Like Peptide 1 / Q000097:blood*; D006801:Humans; D015918:Infusion Pumps, Implantable; D008264:Macrophages / Q000502:physiology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis; D020780:Matrix Metalloproteinase 9 / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068900:Sitagliptin Phosphate / Q000494:pharmacology / Q000627:therapeutic use*; D020298:U937 Cells
chemical_list: D001057:Apolipoproteins E; D054873:Dipeptidyl-Peptidase IV Inhibitors; D017382:Reactive Oxygen Species; D000804:Angiotensin II; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; C545245:Dpp4 protein, mouse; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000068900:Sitagliptin Phosphate