Abstract 11457: Dipeptidyl Peptidase-4 Inhibitor, Des-Fluoro-Sitagliptin, Improved Endothelial Function through Enhancing Action of Glucagon-Like Peptide-1 in vivo and in vitro
Background: Dipeptidyl peptidase-4 inhibitors (DPP4-Is), has been applied to treat diabetes mellitus (DM) through increasing plasma levels of active glucagon-like peptide-1 (GLP-1). We hypothesized that DPP4-I, Des-Fluoro-Sitagliptin (DF-sitagliptin), could exhibit cardiovascular benefits through improving endothelial dysfunction.
Methods and Results: Apolipoprotein E-deficient mice were fed by high fat diet with or without DF-sitagliptin (200mg/kg/day) for 7 weeks. DF-sitagliptin-treatment significantly improved acetylcholine-induced endothelium-dependent vaso-relaxation in aortic rings compared to vehicle-treatment (89.9±9.7% vs. 79.2±10.2% relaxation at 10-4M; n=7 each, P<0.05) independent from fasting blood glucose and lipid profiles. The maximum relaxation by acetylcholine was significantly correlated with fasting plasma levels of active GLP-1 (r=0.53, n=14, P<0.05). DF-sitagliptin treatment significantly increased endothelial nitric oxide synthase (eNOS) phosphorylation in aortae (1.46±0.16 fold, P<0.05). In human coronary artery endothelial cells, DF-sitagliptin (2μ M) -enhanced GLP-1 activity (10pM) sustained eNOS phosphorylation (1.47±0.04 fold at 10 min, n=6, P<0.01). Pretreatment with MDL12,330-A (5μ M) or H89 (5μ M) significantly suppressed the enhancing effects of DF-sitagliptin on GLP-1-induced eNOS phosphorylation. GLP-1 combined with DF-sitagliptin decreased endothelial senescence assessed by senescence-associated β-galactosidase staining (73.4±2.4% vs. 88.6±2.8%, n=6, P<0.01) and H2O2-induced apoptosis (11.0±0.6% vs. 23.6±1.4%, n=6, P<0.01) compared to GLP-1 alone, and NG-nitro-L-arginine methyl ester (1mM) significantly attenuated the inhibitory effects of DF-sitagliptin/GLP-1 on senescence and apoptosis. In the clinical study, additional treatment of sitagliptin (50mg/day, mean 3.5 months) significantly improved endothelial function assessed by reactive hyperemia peripheral arterial tonometry in uncontrolled DM patients (n=14, pre 1.49 [1.37-1.66], post 1.82 [1.49-2.21], P<0.01).
Conclusions: DPP4-I, DF-sitagliptin, significantly improved endothelial functions in in-vivo and in-vitro, potentially exhibiting beneficial effects on cardiovascular system.
- © 2011 by American Heart Association, Inc.