Abstract 671: Glucagon-like Peptide-1 Inhibits Abdominal Aortic Aneurysm Development

Abstract

Objective: It has been shown that glucagon-like peptide-1 (GLP-1) signaling is protective effect in cardiovascular system. Thus, it is important to elucidate the underlying molecular mechanisms to develop a pharmacological treatment. We examined the effect of DPP-4 inhibitor (Alogliptin) and GLP-1 receptor analog (Lixisenatide) on AAA development.

Methods: Thirty AAA model rats were divided into 2 groups: a control group (water) and alogliptin group (3 mg/kg/day). Alogliptin administration by gastric gavage was started at 7 days after aneurysm preparation. On day 14, plasma GLP-1 concentrations were measured with an ELISA. Furthermore we investigated the effect of lixisenatide to elucidate the role of GLP-1 signaling on AAA development, 42 rats were divided into 3 groups: a control group (saline), a low-dose group (10 μg/kg/day), and a high-dose group (100 μg/kg/day). Lixisenatide subcutaneous injection was started at 7 days after aneurysm preparation. Reactive oxygen species (ROS) expression in all groups was evaluated by dihydroethidium staining, and 8-hydroxydeoxyguanosine (8-OHdG) the oxidation product of DNA by immunochemical staining. The effect of GLP-1 signaling on the inflammatory response was also analyzed. Histopathological examinations were performed on day 28 and the AAA dilatation ratio was calculated.

Results: On day 14, plasma GLP-1 concentrations were significantly increased by alogliptin (6.3 ± 0.8 pmol/L in Control group, 7.6 ± 0.9 pmol/L in Alogliptin group, p < 0.05). ROS expression and 8-OHdG-positive cells in aneurysm walls were significantly decreased by alogliptin and lixisenatide. They decreased ERK expression in Western blot analysis, and reduced mRNA expression of tumor necrosis factor-α and matrix metallo-proteinases. CD68 positive macrophages infiltration in aneurysm walls were also decreased with treatment. On day 28, alogliptin (199.2 ± 10.0 % in Control group, 155.1 ± 2.3 % in Alogliptin group, p < 0.01) and lixisenatide (188.0 ± 5.6 % in Control, 162.0 ± 6.0 % in Low-dose, and 151.5 ± 4.9 % in High-dose, p < 0.01) prevented aneurysm development.

Conclusion: GLP-1 inhibits AAA development through anti-oxidant and anti-inflammatory effects, and it might be a potent pharmacological target for AAA treatment.