Division of Cardiology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 83301, Taiwan.
Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 83301, Taiwan.
Cells. 2019 Jun 14;8(6):589. doi: 10.3390/cells8060589.
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.
高血糖导致内皮功能障碍，这是糖尿病血管并发症发展的初始过程。在损伤后，内皮细胞经历内皮到间充质转化（EndMT），失去其特定标志物，并获得间充质表型。本研究探讨了胰高血糖素样肽 1（GLP-1）受体激动剂利拉鲁肽对链脲佐菌素诱导的糖尿病小鼠EndMT 抑制和新生内膜形成的影响。用或不用利拉鲁肽处理右侧颈总动脉丝线诱导血管损伤的糖尿病小鼠 4 周。通过组织学评估评估新生内膜形成和再内皮化的程度。内皮命运追踪显示，在内皮源性细胞通过体内 EndMT 有助于新生内膜形成。在糖尿病小鼠模型中，利拉鲁肽减弱了丝线损伤诱导的新生内膜形成并加速了再内皮化。在体外，高葡萄糖条件（30mmol/L）引发人脐静脉内皮细胞（HUVEC）的形态变化和间充质标志物表达，利拉鲁肽或激活素受体样 5（ALK5）抑制剂 SB431542 减弱了这种表达。通过 Compound C 抑制 AMP 激活的蛋白激酶（AMPK）信号通路，削弱了利拉鲁肽对 EndMT 的抑制作用。总之，利拉鲁肽通过抑制 EndMT 部分减轻糖尿病小鼠的新生内膜形成，扩展了利拉鲁肽的潜在治疗作用。
