Ding Zerui, Yang Chunru, Zhai Xiaojun, Xia Yuqi, Liu Jieying, Yu Miao
Key Laboratory of Endocrinology National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Center for Biomarker Discovery and Validation, National Infrastructures for Translational Medicine (PUMCH), Institute of Clinical Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
Int J Mol Sci. 2025 Mar 6;26(5):2367. doi: 10.3390/ijms26052367.
Diabetes wound healing presents several significant challenges, which can complicate recovery and lead to severe consequences. Polyethylene glycol loxenatide (PEG-loxe), a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), shows cardiovascular benefits, yet its role in diabetic wound healing remains unclear. Diabetic mice received PEG-loxe (0.03 mg/kg/week, i.p.) for three months. Glucose metabolism was evaluated using the insulin tolerance test (ITT) and oral glucose tolerance test (OGTT). Wound closure rates and angiogenesis-related proteins were analyzed. Serum proteomics was performed using the Olink assay to evaluate systemic inflammation. In vitro, human endothelial progenitor cells (EPCs) were exposed to high glucose and palmitic acid, with or without PEG-loxe treatment. EPC tube formation and migratory capacity were evaluated using the tube formation assay and migration assay, respectively. Levels of nitric oxide (NO) and phosphorylated endothelial nitric oxide synthase (p-eNOS) were quantified. Mitochondrial reactive oxygen species (ROS) production and mitochondrial membrane potential were assessed using MitoSOX and JC-1 staining. Cellular respiratory function was analyzed via the Seahorse XF assay. Autophagy was evaluated by examining the expression of autophagy-related proteins and the colocalization of mitochondria with lysosomes. PEG-loxe improved glucose tolerance, accelerated wound closure, and upregulated the hypoxia-inducible factor-1α/vascular endothelial growth factor/stromal cell-derived factor-1 axis (HIF-1α/VEGF/SDF-1) in diabetic mice. Serum proteomics revealed reduced pro-inflammatory markers and elevated anti-inflammatory IL-5. In vitro, PEG-loxe restored EPC function by enhancing NO production, reducing mitochondrial ROS, improving cellular respiratory function, and restoring autophagic flux. These findings suggest that PEG-loxe offers therapeutic benefits for diabetic wound healing by downregulating systemic inflammation, enhancing angiogenesis, and improving mitochondrial quality control in EPCs, highlighting GLP-1RAs as potential therapies for diabetic vascular complications.
糖尿病伤口愈合面临若干重大挑战，这些挑战会使恢复过程复杂化并导致严重后果。聚乙二醇洛塞那肽（PEG-loxe）是一种长效胰高血糖素样肽-1受体激动剂（GLP-1RA），具有心血管益处，但其在糖尿病伤口愈合中的作用仍不清楚。给糖尿病小鼠腹腔注射PEG-loxe（0.03毫克/千克/周），持续三个月。使用胰岛素耐量试验（ITT）和口服葡萄糖耐量试验（OGTT）评估葡萄糖代谢。分析伤口闭合率和血管生成相关蛋白。使用Olink检测法进行血清蛋白质组学分析以评估全身炎症。在体外，将人内皮祖细胞（EPC）暴露于高糖和棕榈酸中，分别给予或不给予PEG-loxe处理。分别使用管形成试验和迁移试验评估EPC的管形成能力和迁移能力。对一氧化氮（NO）和磷酸化内皮型一氧化氮合酶（p-eNOS）水平进行定量。使用MitoSOX和JC-1染色评估线粒体活性氧（ROS）产生和线粒体膜电位。通过海马XF检测法分析细胞呼吸功能。通过检查自噬相关蛋白的表达以及线粒体与溶酶体的共定位来评估自噬。PEG-loxe改善了糖尿病小鼠的葡萄糖耐量，加速了伤口闭合，并上调了缺氧诱导因子-1α/血管内皮生长因子/基质细胞衍生因子-1轴（HIF-1α/VEGF/SDF-1）。血清蛋白质组学显示促炎标志物减少，抗炎性白细胞介素-5升高。在体外，PEG-loxe通过增强NO产生、减少线粒体ROS、改善细胞呼吸功能和恢复自噬通量来恢复EPC功能。这些发现表明，PEG-loxe通过下调全身炎症、增强血管生成和改善EPC中的线粒体质量控制，为糖尿病伤口愈合提供治疗益处，突出了GLP-1RAs作为糖尿病血管并发症潜在治疗方法的可能性。
