High glucose and elevated fatty acids suppress signaling by the endothelium protective ligand angiopoietin-1

Pre-diabetes is characterized by hyperglycemia and dyslipidemia; it is associated with increased cardiovascular disease and endothelial dysfunction. Angiopoietin-1 (Ang1), a ligand for endothelial receptor, is a potent vascular protective factor important in maintaining normal endothelial function. The aim of the study was to examine the influence of elevated glucose and fatty acid concentrations on angiopoietin signaling in human cardiac microvascular endothelial cells. Incubation with 30 mM glucose caused 50% suppression in the ability of Ang1 to activate Tie2-receptor phosphorylation without any decrease in Tie2 expression or increased internalization in microvascular endothelial cells. Examination of downstream signaling revealed inhibition of Ang1-dependent Akt phosphorylation. By contrast, Ang1 activation of Erk1/2 signaling was not affected by hyperglycemia. Similar suppression of Ang1-dependent activation of Akt by hyperglycemia was observed in large vessel human endothelial cells. Incubation of microvascular endothelial cells with 200 μM palmitic acid significantly inhibited Ang1-dependent Akt phosphorylation without affecting phosphorylation of the Tie-2 receptor or of ERK1/2. Therefore, contrary to hyperglycemia, palmitate acted exclusively downstream of the receptor. The present findings suggest a mechanism by which increased glucose or fatty acids may suppress vascular protection by Ang1 and predispose to endothelial dysfunction and vascular disease.