Liraglutide via Activation of AMP-Activated Protein Kinase-Hypoxia Inducible Factor-1α-Heme Oxygenase-1 Signaling Promotes Wound Healing by Preventing Endothelial Dysfunction in Diabetic Mice

Background/Aims: Diabetic foot ulcers (DFUs) present a major challenge in clinical practice, and hyperglycemia-induced angiogenesis disturbance and endothelial dysfunction likely exacerbate DFUs. The long-acting glucagon-like peptide-1 (GLP-1) analog liraglutide (Lira) is a potential activator of AMP-activated protein kinase (AMPK) that appears to enhance endothelial function and have substantial pro-angiogenesis and antioxidant stress effects. Therefore, in this study, we aimed to investigate whether the protective role of Lira in diabetic wound healing acts against the mechanisms underlying hyperglycemia-induced endothelial dysfunction and angiogenesis disturbance. Methods: Accordingly, db/db mice were assessed after receiving subcutaneous Lira injections. We also cultured human umbilical vein endothelial cells (HUVECs) in either normal or high glucose (5.5 or 33 mM glucose, respectively) medium with or without Lira for 72 h. Results: An obvious inhibition of hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance was observed; follow by a promotion of diabetic wound healing under Lira treatment combined with restored hyperglycemia-impaired AMPK signaling pathway activity. AMPKα1/2 siRNA and Compound C (Cpd C), an inhibitor of AMPK, abolished both Lira-mediated endothelial protection and pro-angiogenesis action, as well as the diabetic wound healing promoted by Lira. Furthermore, hypoxia inducible factor-1α (Hif-1α; transcription factors of AMPK substrates) knockdown in HUVECs and db/db mice demonstrated that Lira activated AMPK to prevent hyperglycemia-triggered endothelial dysfunction and angiogenesis disturbance, with a subsequent promotion of diabetic wound healing that was Hif-1α–heme oxygenase-1 (HO-1) axis-dependent. Taken together, these findings reveal that the promotion of diabetic wound healing by Lira occurs via its AMPK-dependent endothelial protection and pro-angiogenic effects, which are regulated by the Hif-1α–HO-1 axis.