Antiatherogenic effects of liraglutide in hyperglycemic apolipoprotein E-null mice via AMP-activated protein kinase-independent mechanisms.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) exert potent glucose-lowering effects without increasing risks for hypoglycemia and weight gain. Preclinical studies have demonstrated direct antiatherogenic effects of GLP-1RAs in normoglycemic animal models; however, the underlying mechanisms in hyperglycemic conditions have not been fully clarified. Here we aimed to elucidate the role of AMP-activated protein kinase (AMPK) in antiatherogenic effects of GLP-1RAs in hyperglycemic mice. Streptozotocin-induced hyperglycemic apolipoprotein E-null mice were treated with vehicle, low-dose liraglutide (17 nmol·kg·day), or high-dose liraglutide (107 nmol·kg·day) in and the AMPK inhibitor dorsomorphin, dorsomorphin + low-dose liraglutide, or dorsomorphin + high-dose liraglutide in . Four weeks after treatment, aortas were collected to assess atherosclerosis. In , metabolic parameters were similar among the groups. Assessment of atherosclerosis revealed that high-dose liraglutide treatments reduced lipid deposition on the aortic surface and plaque volume and intraplaque macrophage accumulation at the aortic sinus. In , liraglutide-induced AMPK phosphorylation in the aorta was abolished by dorsomorphin; however, the antiatherogenic effects of high-dose liraglutide were preserved. In cultured human umbilical vein endothelial cells, liraglutide suppressed tumor necrosis factor-induced expression of proatherogenic molecules; these effects were maintained under small interfering RNA-mediated knockdown of AMPKα1 and in the presence of dorsomorphin. Conversely, in human monocytic U937 cells, the anti-inflammatory effects of liraglutide were abolished by dorsomorphin. In conclusion, liraglutide exerted AMPK-independent antiatherogenic effects in hyperlipidemic mice with streptozotocin-induced hyperglycemia, with the possible involvement of AMPK-independent suppression of proatherogenic molecules in vascular endothelial cells.