Abstract 239: Dpp-4 Inhibitor Alogliptin Prevents Abdominal Aortic Aneurysm Formation and Development in Rat Model

Abstract

Objective Dipeptidyl peptidase-4 (DPP-4) inhibitor, a novel anti-diabetic drug, has been proved to have a cardioprotective effect on ischemia-reperfusion injury through an antioxidant effect. Although we reported reactive oxygen spices (ROS) play a crucial role in AAA formation and development, the effect of DPP-4 inhibitor on AAA has not been investigated. In this study, we examined the effect of DPP-4 inhibitor alogliptin on experimental AAA rat model. Methods An AAA model induced with intraluminal elastase and extraluminal calcium chloride was created using 48 rats. Thirty-six rats were divided into 3 groups; a low dose (group LD; 1mg/kg/day), high-dose (group HD;3mg/kg/day), and control (group C; pure water). Alogliptin was administered by gastric gavage once per day beginning 3 days before surgery. The remaining 12 rats received a delayed alogliptin administration (group DA-LD; 1mg/kg/day, group DA-HD; 3mg/kg), starting on day 7 after aneurysm preparation up to 28 days. On day 7, ROS expression was semi-quantified by dihydroethidium staining and the oxidative product of DNA induced by ROS, 8-hydroxydeoxyguanosine (8-OHdG), by immunohistochemical staining. Histopathological examination was performed on day 28, and AAA dilatation ratio was calculated. Results On day 7, ROS expression were reduced (4.6±0.6 in group C, 2.7±0.3 in group LD, 1.7±0.5 in group HD; p<0.001) and there were fewer 8-OHdG positive cells in alogliptin treated samples (138.1±7.4 in group C, 102.5±4.5 in group LD, 66.1±4.5 in group HD; p<0.001). The treatment reduced messenger RNA expression and activity of matrix metallo-proteinases 2 and 9 in aneurysm walls. On day 28, aortic walls in group LD and HD were less dilated than those in group C (199.2±11.8 % in group C, 159.6±2.8 % in group LD, 147.1±1.9 % in group HD; p<0.02). Delayed alogliptin administration prevented further aneurysm dilatation compared with the aortic walls in group C at day 7 (158.9±8.5 % in group C at day 7, 160.1±14.3 % in group DA-LD, 155.1±2.6 % in group DA-HD; n.s.). Conclusion DPP-4 inhibitor alogliptin treatment starting on day 7 after aneurysm preparation completely inhibited aneurysm development. Alogliptin could be effective pharmaceutical agent against AAA in clinical practice.