Chinese-American Research Institute for Diabetic Complications, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
The Second School of Medicine, Wenzhou Medical University, Wenzhou 325027, China.
Cells. 2022 Nov 29;11(23):3821. doi: 10.3390/cells11233821.
The impairment in endothelial progenitor cell (EPC) functions results in dysregulation of vascular homeostasis and dysfunction of the endothelium under diabetic conditions. Improving EPC function has been considered as a promising strategy for ameliorating diabetic vascular complications. Liraglutide has been widely used as a therapeutic agent for diabetes. However, the effects and mechanisms of liraglutide on EPC dysfunction remain unclear. The capability of liraglutide in promoting blood perfusion and angiogenesis under diabetic conditions was evaluated in the hind limb ischemia model of diabetic mice. The effect of liraglutide on the angiogenic function of EPC was evaluated by cell scratch recovery assay, tube formation assay, and nitric oxide production. RNA sequencing was performed to assess the underlying mechanisms. Liraglutide enhanced blood perfusion and angiogenesis in the ischemic hindlimb of db/db mice and streptozotocin-induced type 1 diabetic mice. Additionally, liraglutide improved tube formation, cell migration, and nitric oxide production of high glucose (HG)-treated EPC. Assessment of liraglutide target pathways revealed a network of genes involved in antioxidant activity. Further mechanism study showed that liraglutide decreased the production of reactive oxygen species and increased the activity of nuclear factor erythroid 2-related factor 2 (Nrf2). Nrf2 deficiency attenuated the beneficial effects of liraglutide on improving EPC function and promoting ischemic angiogenesis under diabetic conditions. Moreover, liraglutide activates Nrf2 through an AKT/GSK3β/Fyn pathway, and inhibiting this pathway abolished liraglutide-induced Nrf2 activation and EPC function improvement. Overall, these results suggest that Liraglutide represents therapeutic potential in promoting EPC function and ameliorating ischemic angiogenesis under diabetic conditions, and these beneficial effects relied on Nrf2 activation.
内皮祖细胞 (EPC) 功能障碍会导致糖尿病状态下血管稳态失调和内皮功能障碍。改善 EPC 功能被认为是改善糖尿病血管并发症的有前途的策略。利拉鲁肽已被广泛用作糖尿病的治疗剂。然而，利拉鲁肽对 EPC 功能障碍的影响和机制尚不清楚。在糖尿病小鼠的后肢缺血模型中评估了利拉鲁肽在糖尿病情况下促进血液灌注和血管生成的能力。通过细胞划痕恢复试验、管形成试验和一氧化氮产生来评估利拉鲁肽对 EPC 血管生成功能的影响。进行 RNA 测序以评估潜在机制。利拉鲁肽增强了 db/db 小鼠和链脲佐菌素诱导的 1 型糖尿病小鼠缺血后肢的血液灌注和血管生成。此外，利拉鲁肽改善了高糖 (HG) 处理的 EPC 的管形成、细胞迁移和一氧化氮产生。对利拉鲁肽靶途径的评估揭示了涉及抗氧化活性的基因网络。进一步的机制研究表明，利拉鲁肽减少了活性氧的产生，并增加了核因子红细胞 2 相关因子 2 (Nrf2) 的活性。Nrf2 缺乏减弱了利拉鲁肽改善 EPC 功能和促进糖尿病情况下缺血性血管生成的有益作用。此外，利拉鲁肽通过 AKT/GSK3β/Fyn 通路激活 Nrf2，抑制该通路可消除利拉鲁肽诱导的 Nrf2 激活和 EPC 功能改善。总体而言，这些结果表明，利拉鲁肽在促进 EPC 功能和改善糖尿病情况下缺血性血管生成方面具有治疗潜力，这些有益作用依赖于 Nrf2 的激活。
