Actions of Liraglutide on Vascular Endothelial Cells Play a Central Role in the Suppression of Atherosclerosis in Diabetic Mice

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been shown to exert direct anti-atherosclerotic effects through multiple actions on various cells. However, it is unclear which action is crucial. We investigated the role of the anti-atherogenic effects of liraglutide (Lira) on vascular endothelial cells (VECs) in vivo.

Methods: Streptozotocin-induced diabetic apolipoprotein E-null mice (male, 20 weeks) were randomly assigned to treatment with saline or Lira (17 nmol/kg/d) and underwent femoral artery (FA) wire injury to remove VECs. Thioglycolate-exudated peritoneal macrophages and vascular samples (aorta, FA, and right brachiocephalic artery [RBCA]) were collected 4 weeks after treatment.

Results: In the Lira group, active GLP-1 levels were significantly higher (4.7 ± 1.1 vs. 2.8 ± 0.3 pmol/L) and levels of HbA1c (8.9 ± 0.4% vs. 8.3 ± 0.5%) and total cholesterol (492 ± 8 vs. 457 ± 19 mg/dL) were significantly lower than in controls. Lira significantly reduced the atherosclerotic plaque (oil red O [ORO]-stained area) on the surface of the whole aorta by 36% and the plaque volume and intraplaque macrophage infiltration in the aortic root by 56% and 55%, respectively. Additionally, Lira suppressed the expression of inflammatory cytokines in macrophages by 40-45% (p < 0.05) and the expression of inflammatory cytokines in the RBCAs, which are prone to lesion, plaque formation, and rupture. In FA, no plaque was observed in uninjured lesions, while severe plaque formation occurred in injured lesions. In contrast, Lira failed to suppress plaque volume or neointimal thickening in FAs where the VECs were removed (ORO-stained area/vascular wall area: 0.51 ± 0.vs. 0.55 ± 0.08, neointimal area/medial area: 2.4 ± 1.2 vs. 2.6 ± 0.7), indicating that Lira cannot suppress atherosclerosis independent of VECs.

Conclusions: Of the multiple actions on various cells, VECs play a central role in the suppression of atherosclerosis mediated by Lira.