Liraglutide restores angiogenesis in palmitate-impaired human endothelial cells through PI3K/Akt-Foxo1-GTPCH1 pathway

•Liraglutide restores endothelial tube formation impaired by palmitate in HUVECs.•Liraglutide upregulates GTPCH1 and eNOS levels, thus promoting angiogenesis.•The liraglutide-mediated regulation of GTPCH1 and eNOS requires Foxo1 inactivation.•The effect of liraglutide on angiogenesis is mediated via PI3K/Akt-Foxo1 pathway.

Glucagon-like peptide-1 (GLP-1) and its analogues have a beneficial role in cardiovascular system. Here, we aimed to investigate whether liraglutide, a GLP-1 analogue, modulated angiogenesis impaired by palmitic acid (PA) in cultured human umbilical vein endothelial cells (HUVECs). Cells were incubated with liraglutide (3-100 nmol/L) in the presence of PA (0.5 mmol/L), and endothelial tube formation was observed and quantified. The protein levels of signaling molecules were analyzed and the specific inhibitors were used to identify the signaling pathways through which liraglutide affected angiogenesis. Results showed that liraglutide ameliorated endothelial tube formation impaired by PA in HUVECs in a dose-dependent manner. Meanwhile, liraglutide increased the phosphorylation of Akt and forkhead box O1 (Foxo1), and upregulated the levels of guanosine 5′-triphosphate cyclohydrolase 1 (GTPCH1) and endothelial nitric oxide synthase (eNOS) in PA-impaired HUVECs. Notably, addition of the PI3K inhibitor LY294002, Foxo1 nuclear export inhibitor trifluoperazine dihydrochloride (TFP), GTPCH1 inhibitor 2,4-diamino-6-hydroxypyrimidine (DAHP) or NOS inhibitor N-nitro-l-arginine-methyl ester (L-NAME) eliminated the angiogenic effect of liraglutide. Moreover, either LY294002 or TFP abolished the liraglutide-induced upregulation of GTPCH1 and eNOS protein levels. In conclusion, liraglutide restores angiogenesis in PA-impaired HUVECs. The effect is mediated via upregulation of GTPCH1 and eNOS levels in a PI3K/Akt-Foxo1-dependent mechanism.