Abstract 10008: Combined Treatment with Dipeptidyl-Peptidase-4 Inhibitor and Glucagon-Like Peptidase-1 Attenuates Endothelial Inflammation through Activation of AMP-Activated Protein Kinase/Endothelial-Nitric Oxidase Synthase Pathway
Background: Inflammation plays a crucial role in pathogenesis of diabetes mellitus (DM) and atherogenesis. Adenosine monophosphate activated protein kinase (AMPK) might be a key regulator of glucose metabolism and endothelial functions. Dipeptidyl peptidase-4 inhibitors (DPP4-Is), have recently been applied to treat DM through increasing plasma levels of active glucagon-like peptide-1 (GLP-1). Several studies have shown beneficial effects of GLP-1 analogues and DPP4-Is on cardiovascular system. We hypothesized that DPP4-I, Des-Fluoro-Sitagliptin (DFS), could exhibit anti-inflammatory effects on endothelial cells through activation of AMPK.
Methods and Results: In cultured human coronary artery endothelial cells, GLP-1 (10pM, physiological concentration) combined with DFS (2μ M, medically achievable concentration) increased phosphorylation of AMPK compared to GLP-1 alone. The GLP-1/DFS-induced phosphorylation of AMPK was significantly increased from 20min after stimulation and lasting for 120min with peak activation at 60min (peak: 2.94±1.03 fold, P<0.05). Liver kinase B1, an upstream regulator of AMPK, was concordantly phosphorylated by GLP-1/DFS from 5min to 20min(peak: 1.77±0.20 fold, P<0.05). Phosphorylation of endothelial nitric oxide synthase (eNOS) was significantly increased by GLP-1/DFS compared to GLP-1 alone (1.29±0.05-fold, n=3-5, P<0.05). This effect of GLP-1/DFS on eNOS activation was inhibited by a selective AMPK blocker; Compound-C (10μ M). GLP-1/DFS significantly reduced the mRNA levels of basal expression and those induced by interleukin (IL)-1β (10ng/ml) of intercellular adhesion molecule-1 (basal: -11.0±4.5%, P<0.05, IL-1β: -20.0±7.5%, P<0.05, n=6) and vascular cell adhesion molecule-1 (basal: -13.1%±5.7%, P<0.05, IL-1β: -28.0±10.3%, P<0.05, n=6) compared to GLP-1 alone. This anti-inflammatory effects of GLP-1/DFS were abolished by using eNOS inhibitor; NG-nitro-L-arginine methyl ester (1mM) or Compound-C (10µM).
Conclusion: DPP4-I, DF-Sitagliptin, enhanced the actions of GLP-1 on endothelium leading to reduce endothelial inflammation through the AMPK/eNOS pathway. Sitagliptin could exhibit anti-atherogenic effects via improving endothelial inflammation in patients with DM.
- © 2012 by American Heart Association, Inc.