Dipeptidyl-peptidase-4 inhibitor, alogliptin, attenuates arterial inflammation and neointimal formation after injury in low-density lipoprotein (LDL) receptor-deficient mice.

Background: The results of recent studies suggest that dipeptidyl-peptidase-4 inhibitors have antiatherogenic effects. However, whether or not dipeptidyl-peptidase-4 inhibitors could suppress arterial inflammation and intimal hyperplasia after injury remains undetermined. The present study aims to clarify the anti-inflammatory effects of the dipeptidyl-peptidase-4 inhibitor, alogliptin (AGP), on the arteries of atherogenic low-density lipoprotein receptor-deficient (LKO) mice.
Methods and Results: We compared intimal hyperplasia in LKO mice 2 weeks after femoral artery injury using an external vascular cuff model. All mice received oral injection of AGP (20 mg/kg per day) or normal saline (control) once daily for 14 days. Fasting blood sugar levels, serum cholesterol levels, or blood pressure did not significantly differ between the 2 groups. Plasma levels of active glucagon-like peptide-1 were higher in the AGP than in the control LKO mice (22.2±1.9 versus 15.6±0.9 pg/mL; P<0.05). Compared with saline, AGP significantly reduced intimal hyperplasia (1087±127 versus 1896±140 μm(2); P<0.001) as well as the intima/media ratio (0.08±0.01 versus 0.16±0.02; P<0.001). Immunostaining showed that AGP reduced proliferating cells (proliferating cell nuclear antigen-positive nuclei; P<0.001), percent smooth-muscle cell area (α-SMA-positive cells; P<0.001), inflammatory cells infiltration (lymphocyte antigen 6 complex-positive cells; P<0.05), tumor necrosis factor-α expression (P<0.05), and percent phospho-NF-κB-positive cell compared with saline. Levels of tumor necrosis factor -α (0.5-fold P<0.05), monocyte chemoattractant protein 1 (0.3-fold P<0.01), and interleukin-1β (0.2-fold P<0.05) mRNA were lower in the injured arteries of the AGP than in the control group.
Conclusions: AGP appeared to suppress neointimal formation by inhibiting inflammation, independently of its effects on glucose or cholesterol metabolism in atherogenic LKO mice.
(© 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)