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.
Highlights
Diabetes mellitus (DM) causes hyperglycaemia and systemic inflammation, leading to endothelial dysfunction [1,2,3]
The inhibition of AMPK by Compound C attenuated the liraglutide-mediated effects on signal transduction (p-AMPK and p-Smad2) and endothelial-to-mesenchymal transition (EndMT) marker expression (CD31, SM22α, Snail, and vimentin) (Figure 6b,c). These results indicate that liraglutide reverses high glucose (HG)+IL-1β-induced EndMT via the AMPK pathway
Our results show that HG condition-treated human umbilical vein endothelial cells (HUVECs) acquired spindle morphology and with previous reports that HG induced a loss of endothelial phenotype in HUVECs [16,31]
Summary
Diabetes mellitus (DM) causes hyperglycaemia and systemic inflammation, leading to endothelial dysfunction [1,2,3]. Endothelial damage is the initial process in the progression of diabetic vascular complications [4,5]. The endothelial origin of mesenchymal or fibroblast-like cells can be characterized by the loss of. Cells 2019, 8, 589 cell-cell junctions, acquisition of invasive and migratory capacities, loss of endothelial markers (e.g., CD31, Tie, Tie, Vascular endothelial (VE)-Cadherin, and von Willebrand factor (vWF)), and gain of mesenchymal markers (e.g., fibroblast-specific protein 1(FSP-1), alpha-smooth muscle actin (a-SMA), smooth muscle-22alpha actin (SM22α), N-cadherin, and vimentin) [7,8,9,10]. Recent studies have revealed that inflammation and diabetic conditions, such as high glucose, trigger the trans-differentiation of endothelial cells into mesenchymal-like cells [13,14,15,16]. The EndMT process may be the initial stage of neointima hyperplasia under diabetic conditions
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