Abstract 21648: DPP-4 Inhibition Reduces Atherosclerosis in LDLRKO Mice Through Pleiptropic Effects on Blood Pressure and Modulation of Immune Function
Objective: Dipeptidyl-peptidase-4 (DPP4, CD26) inhibitors reduce post-prandial glycemia via inhibition of glucagon-like peptide-1 (GLP-1) degradation. DPP4 inhibition (DPP4i) may have anti-inflammatory effects through the modulation of GLP-1 receptor function and non GLP-1 pathways in immune cells. We hypothesized that DPP4i may have protective effects in atherosclerosis.
Methods: Male LDLRKO mice were randomized to a high fat diet for 8-weeks and then treated with placebo or oral alogliptin (12/group), a high affinity DPP4 inhibitor (40mg/kg/day) for 12-weeks. Metabolic parameters, blood pressure, vascular function, atherosclerosis burden and indices of inflammation were obtained in the thoracic aorta. CD11b+ Ly6hi monocytes in blood/marrow and in aorta were quantified and inflammatory gene expression in CD11b+ monocytes assessed.
Results: DPP4i improved fasting and post-glucose load indices, insulin resistance (HOMA-IR), beta-cell function (HOMA-β) triglyceride and HDL cholesterol measures. Plasma adiponectin increased with DPP4i (6.61±0.9 vs. 4.3±0.2 μg/ml in placebo, p<0.05) along with reduction in systolic blood pressure (111±4 vs. 118±10 mm Hg, DPP4i vs. placebo p<0.05). Acetylcholine and insulin dependent vasorelaxation of the thoracic aorta was improved (maximal relaxation Ach= 90±6 vs. 54±8; Insulin=84±4 vs. 61±7 in DPP4i vs. placebo respectively, p < 0.05 for both agonists) DPP4i reduced plaque burden at the aortic sinus (0.64±0.08 vs. 0.37±0.07 μm2 in DPP4i vs. placebo, p<0.05) with concomitant reductions in CD11b+, and CD206+ macrophages in aorta when assessed by flow-cytometry (CD11b+= 52±8 vs. 40±4% CD206+=69±7 vs. 56±7% of total mononuclear cells in DPP4i vs. placebo respectively, p < 0.05 for both). Bone marrow derived CD11b+ cells expressed DPP4 transcript with increase in mRNA levels in the chronic DPP4i treatment group. Additionally there was suppression of CCR2, TNFα, IFNγ and IL-6 expression in response to DPP4i. In-vitro transmigration assays in cultured human monocytes revealed suppression of monocyte migration in response to CCL2 by DPP4i.
Conclusions: DPP4i exerts anti-atherosclerotic effects via pleiotropic effects on blood pressure and inflammatory monocyte activation and migration.
- © 2010 by American Heart Association, Inc.