A Dipeptidyl Peptidase-4 Inhibitor but not Incretins Suppresses Abdominal Aortic Aneurysms in Angiotensin II-Infused Apolipoprotein E-Null Mice

作者：Kohashi Kyoko; Hiromura Munenori; Mori Yusaku; Terasaki Michishige; Watanabe Takuya; Kushima Hideki; Shinmura Kyoko; Tomoyasu Masako; Nagashima Masaharu; Hirano Tsutomu^*

来源：Journal of Atherosclerosis and Thrombosis, 2016, 23(4): 441-454.

DOI：10.5551/jat.31997

• Abdominal aortic aneurysm
• Incretin
• DPP-4 inhibitor
• Angiotensin II

Aim: 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. (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-1 beta 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.

• 出版日期2016