Abstract 9995: Glucagon-Like-Peptide-1 (GLP-1) Activates AMP-Activated Protein Kinase (AMPK) and Diminishes Inflammation in Human Aortic Endothelial Cells (HAECs)
GLP-1 therapy is primarily prescribed for patients with type 2 diabetes because of its effects on insulin and glucagon secretion resulting in improved glucose control. Recent epidemiological evidence strongly suggests that it may also have cardio- and cerebrovascular benefits; however, the mechanisms responsible for these benefits are not known. AMPK has been implicated as a target for the prevention of cardiovascular disease by virtue of its involvement in lipid metabolism as well as its ability to suppress inflammation and other atherogenic factors. In the present study we examined whether GLP-1 activates AMPK in HAECs and if so, whether it also downregulates inflammatory and atherogenic factors. Initial RT-PCR studies revealed that HAECs express the primary enzyme responsible for GLP-1 degradation, dipeptidyl peptidase-4 (DPP4), the GLP-1 receptor (GLP-1R) and several targets of the GLP-1R signaling cascade. Thus, these cells possess the machinery necessary to transduce GLP-1 signals. Dose and time course experiments revealed that the concurrent addition of GLP-1 at a concentration of 0.3nM, led to the transient activation by phosphorylation of AMPK and its substrate ACC, which peaked at 15 minutes, returned to baseline by 30 minutes and cyclically rose again by 50 minutes. Incubation of HAECs for 24h in a hyperglycemic media (25mM) led to augmented gene levels of vascular cellular adhesion molecule-1 (VCAM-1) and E-selectin, molecules known to be increased during the course of atherogenesis. GLP-1 addition markedly downregulated both the control level and glucose-stimulated increase in VCAM-1 and E-selectin expression observed at 24h. Repetition of this trial using TNFα treatment to induce inflammation showed similar downregulation of VCAM-1/E-selectin expression attributable to GLP-1 addition. Further studies are needed to determine whether the sustained effect of GLP1 is attributable to AMPK, and if so, whether it works by acute effects on metabolism and/or the regulation transcriptional activators and co-activators.
- © 2011 by American Heart Association, Inc.