Liraglutide Inhibits Endothelial-to-Mesenchymal Transition and Attenuates Neointima Formation after Endovascular Injury in Streptozotocin-Induced Diabetic Mice

Abstract

Hyperglycaemia causes endothelial dysfunction, which is the initial process in the development of diabetic vascular complications. Upon injury, endothelial cells undergo an endothelial-to-mesenchymal transition (EndMT), lose their specific marker, and gain mesenchymal phenotypes. This study investigated the effect of liraglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist, on EndMT inhibition and neointima formation in diabetic mice induced by streptozotocin. The diabetic mice with a wire-induced vascular injury in the right carotid artery were treated with or without liraglutide for four weeks. The degree of neointima formation and re-endothelialisation was evaluated by histological assessments. Endothelial fate tracing revealed that endothelium-derived cells contribute to neointima formation through EndMT in vivo. In the diabetic mouse model, liraglutide attenuated wire injury-induced neointima formation and accelerated re-endothelialisation. In vitro, a high glucose condition (30 mmol/L) triggered morphological changes and mesenchymal marker expression in human umbilical vein endothelial cells (HUVECs), which were attenuated by liraglutide or Activin receptor-like 5 (ALK5) inhibitor SB431542. The inhibition of AMP-activated protein kinase (AMPK) signaling by Compound C diminished the liraglutide-mediated inhibitory effect on EndMT. Collectively, liraglutide was found to attenuate neointima formation in diabetic mice partially through EndMT inhibition, extending the potential therapeutic role of liraglutide.

GLP-1 receptor agonists (GLP-1RAs): cardiovascular actions and therapeutic potential

“…GLP-1 treatment protects against EndMT through inhibiting the activation of poly (ADP-ribose) polymerase 1 (PARP-1) which can elicit Smad3 and transforming growth factor (TGF)-β1 responses. Moreover, GLP-1RAs can reverse EndMT induced by high glucose and IL-1β via activating the AMPK pathway, which was evidenced by augmenting an endothelium marker expression (CD31), as well as alleviating mesenchymal markers expression (SM22α (sensitive 22 kDa actin-binding protein of the calponin), vimentin and Snail) [119]. These results indicate that GLP-1RAs have therapeutic effects against EndMT, an important process in atherosclerosis and fibrotic diseases.…”

Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage

“…Recently, several drugs in clinical testing have been reported to inhibit EndMT in various animal disease models (Table 1). These drugs inhibit EndMT by targeting various signaling molecules, such as DPP-4 25,96 , Smad 97 , TGF-β [97][98][99] , AMPK 100 , and other proteins 28,[101][102][103][104][105][106] .…”

“…Vildagliptin, a drug used to treat diabetes, regulates DPP-4-dependent EndMT and showed anti-fibrotic effects in a mouse model of sepsis 25 . Liraglutide, linagliptin, and losartan, which have been approved for treating diabetes and its complications, inhibited EndMT in diabetic mice and diabetic complications in mouse models 96,97,100 . In addition, the GSK inhibitor, CHIR99021, was shown to inhibit radiation-induced EndMT in HUVECs 101 .…”

Epithelial-endothelial transition and endothelial-mesenchymal transition

“…Vildagliptin, an anti-diabetic drug, ameliorates pulmonary fibrosis in lipopolysaccharide-induced lung injury by inhibiting EndoMT (Suzuki et al, 2017). Calcitriol, an active form of vitamin D3, reduces TGFβ-Smad2-mediated EndoMT and fibroblast to myofibroblast transition (Tsai et al, 2019).…”