Gokce Mustafa, Ozturk Civelek Dilek, Vidin Sen Aylin, Guler Eray Metin, Civelek Erkan, Uydes Dogan Birsel Sonmez, Alp Yildirim F Ilkay
Istanbul University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey.
Bezmialem Vakif University, Faculty of Pharmacy, Department of Pharmacology, Istanbul, Turkey.
Cell Biochem Biophys. 2025 Apr 11. doi: 10.1007/s12013-025-01742-1.
Diabetes-related endothelial dysfunction, alteration in cell signaling, increased oxidative stress and activation of pro-inflammatory processes are the main causes of diabetes-related vascular complications. Glucagon-like peptide-1 (GLP-1) and its receptor (GLP-1R) play a crucial role in regulating glucose homeostasis, insulin secretion, and reducing inflammation. GLP-1R agonists have been explored for their potential in mitigating diabetes-related vascular dysfunction. The NOD-like receptor protein 3 (NLRP3) inflammasome, a key protein complex in immune response, activates caspase-1 and promotes proinflammatory cytokine secretion. High glucose levels activate NLRP3 in macrophages via reactive oxygen species and mitochondrial dysfunction. This study aims to investigate the effects of GLP-1 receptor agonist, Liraglutide, on cell proliferation, inflammation, oxidative stress and NLRP3-related signaling pathways in human umbilical vein endothelial cells (HUVEC) and human coronary artery endothelial cell (HCAEC) cultures. HUVEC and HCAEC were incubated with Liraglutide (10 and 100 nM, 48 h) either in normoglycemic (5.5 mM) or hyperglycemic (25 mM) condition. Cell proliferation, oxidative stress, mRNA and protein expressions of ASC, caspase-1, NLRP3 which are. components of NLRP3 inflammasome, were determined. Our results showed that, Liraglutide significantly reduced hyperglycemia-induced oxidative stress, mRNA and protein expressions of NLRP3 inflammasome and proinflammatory cytokine levels, as well as cell membrane damage in HUVEC and HCAEC. Our results indicate that Liraglutide may have the potential on preventing hyperglycemia-induced cellular damage by reducing inflammation and immune response activation both in human venous and arterial endothelial cells.
糖尿病相关的内皮功能障碍、细胞信号改变、氧化应激增加和促炎过程激活是糖尿病相关血管并发症的主要原因。胰高血糖素样肽-1（GLP-1）及其受体（GLP-1R）在调节葡萄糖稳态、胰岛素分泌和减轻炎症方面发挥着关键作用。GLP-1R激动剂已被探索用于减轻糖尿病相关血管功能障碍的潜力。NOD样受体蛋白3（NLRP3）炎性小体是免疫反应中的关键蛋白复合物，可激活半胱天冬酶-1并促进促炎细胞因子分泌。高糖水平通过活性氧和线粒体功能障碍激活巨噬细胞中的NLRP3。本研究旨在探讨GLP-1受体激动剂利拉鲁肽对人脐静脉内皮细胞（HUVEC）和人冠状动脉内皮细胞（HCAEC）培养物中细胞增殖、炎症、氧化应激和NLRP3相关信号通路的影响。将HUVEC和HCAEC在正常血糖（5.5 mM）或高血糖（25 mM）条件下与利拉鲁肽（10和100 nM，48小时）孵育。测定细胞增殖、氧化应激、ASC、半胱天冬酶-1、NLRP3的mRNA和蛋白表达，这些是NLRP3炎性小体的组成成分。我们的结果表明，利拉鲁肽显著降低了高血糖诱导的氧化应激、NLRP3炎性小体的mRNA和蛋白表达以及促炎细胞因子水平，以及HUVEC和HCAEC中的细胞膜损伤。我们的结果表明，利拉鲁肽可能具有通过减少人静脉和动脉内皮细胞中的炎症和免疫反应激活来预防高血糖诱导的细胞损伤的潜力。
