Background: Glucagon like peptide 1 receptor agonists (GLP-1RAs) have anti-atherosclerotic properties, possibly through activation of AMP-activated protein kinase (AMPK) in the vasculature. However, their relationship remains largely unknown.

Methods: Streptozotocin-induced diabetic apolipoproteinE-null mice (male, 20 w) were randomly assigned to six treatment groups: saline (control, C), liraglutide at low or high doses (L- and H-Lira at 17 and 107 nmol/kg/d, respectively), AMPK inhibitor dorsomorphin (AMPKI, 25 mg/kg/d), AMPKI+L-Lira, or AMPKI+H-Lira.

Results: First, we confirmed that AMPKI inhibited H-Lira-induced AMPK phosphorylation in the aorta (1.5-fold). After 4 w, biological parameters were similar, except for HbA1c levels (C 9.8, L-Lira 8.6, H-Lira 8.4%, p<0.05). Both L- and H-Lira suppressed intraplaque macrophage accumulation at the aortic sinus by 60%. H-Lira also suppressed aortic surface plaque area by 40%, which was not significant in L-Lira (25%). In AMPKI-treated mice, biological parameters were similar. AMPKI completely eliminated L-Lira-induced anti-atherogenic effects but did not attenuate H-Lira-induced suppression of atherosclerotic area (38%) and intraplaque macrophage accumulation (63%), suggesting that AMPK mechanisms are L-Lira-dependent and H-Lira-independent. In cultured human vascular endothelial cells, Lira (100 nM) reduced TNF-induced inflammatory cytokine and adhesion molecule expression by 60 to 80%, which was retained at more than 50% after siRNA-knockdown of AMPK (p<0.05). In cultured human monocytic cells (U937), Lira suppressed LPS-induced inflammatory cytokine expression by 30% (p<0.05), which was completely reversed by AMPKI.

Conclusions: Lira suppressed atherosclerosis via AMPK-dependent and -independent mechanisms; AMPK dependency is altered by GLP-1RA dose and cell type.


M. Koshibu: None. Y. Mori: None. H. Kushima: None. M. Hiromura: None. K. Kohashi: None. M. Terasaki: None. T. Hirano: Speaker's Bureau; Self; Novo Nordisk Inc., AstraZeneca.

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