Abstract 14739: Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin (DFS), Improved Endothelial Function and Reduced Atherosclerotic Lesion Formation in Apolipoprotein E-deficient Mice
Background: A new class anti-type 2 diabetes mellitus (DM) drug, dipeptidyl peptidase-4 inhibitors (DPP4-Is), improved glucose metabolisms through increasing plasma levels of active glucagon-like peptide 1 (GLP-1). We investigated cardiovascular effects of DPP4-I, Des-Fluoro-Sitagliptin (DFS), on improving endothelial dysfunction and reducing atherosclerosis in mice.
Methods: Apolipoprotein E-deficient (apoE−/−) mice were fed by high fat diet with or without DFS (200 mg/kg/day). We examined endothelial function by acetylcholine-induced endothelium-dependent vaso-relaxation using aortic rings (7 weeks treat) and atherosclerotic lesion formation in the entire aorta (16 weeks treat). Anti-inflammatory cellular effects of DFS were investigated in cultured THP-1-derived macrophages in-vitro.
Results: DFS-treatment significantly improved endothelial dysfunction in apoE−/− mice compared to vehicle-treated mice (89.9±9.7% versus 79.2±10.2% relaxation at 10−4M; n=6 each, P<0.05). DFS-treatment significantly reduced atherosclerotic lesion area (19.5±6.2% versus 27.8±9.9% n=18 each, P<0.01) independent from fasting blood glucose and lipid profiles in the apoE−/− mice. The fasting levels of active GLP-1 were significantly higher in the mice treated with DFS than those with vehicle (17.8±5.6 versus 10.8±2.9 pg/ml, P<0.01) and negatively correlated with atherosclerotic lesion area (r=−0.38, P<0.05). In cultured human macrophages, DFS (2 μM) significantly enhanced GLP-1-induced cytosolic levels of cyclic adenosine mono-phosphate compared to GLP-1 alone (10 pM) (+33.7±19.1%, n=4–6, P<0.05), resulting significant decrease in production of proinflammatory mediators in response to lipopolysaccharide (10 ng/mL) (interleukin [IL]-1β, −10.7±3.0%, IL-6, −42.9±5.5%, tumor necrosis factor-α, −29.8±9.3%, respectively, n=4–6, P<0.01) but not IL-10 (−3.3±10.1%, P=0.79).
Conclusions: DPP4-I, DFS, significantly improved endothelial function and reduced atherosclerotic lesion formation in apoE−/− mice with high fat diet independent from fasting blood glucose and lipid profiles. Anti-inflammatory effects of DFS on macrophages through enhancing effects of GLP-1 might in part provide cardiovascular benefits in treating DM.
- © 2010 by American Heart Association, Inc.