Background Diabetic chronic wounds are among the most common and serious complications of diabetes and are associated with significant morbidity and mortality. Endothelial-to-mesenchymal transition (EndMT) is a specific pathological state in which endothelial cells are transformed into mesenchymal cells in response to various stimuli, such as high glucose levels and high oxidative stress. Acidic fibroblast growth factor (aFGF), which is a member of the fibroblast growth factor family, possesses strong antioxidant properties and can promote the differentiation of mesenchymal stem cells into angiogenic cells. Therefore, we investigated the role of aFGF in EndMT in diabetic wounds and analysed the underlying mechanisms. Methods A diabetic mouse model was used to verify the effect of aFGF on wound healing, and the effect of aFGF on vascular endothelial cells in a high-glucose environment was examined in vitro. We examined the expression of miR-155-5p in a high-glucose environment and the miR-155 downstream target gene SIRT1 by luciferase reporter assays. Results aFGF promoted wound closure and neovascularization in a mouse model of type 2 diabetes. In vitro, aFGF inhibited the production of total and mitochondrial reactive oxygen species (ROS) in vascular endothelial cells and alleviated epithelial–mesenchymal transdifferentiation in a high-glucose environment. Mechanistically, aFGF promoted the expression of SIRT1 and the downstream targets Nrf2 and HO-1 by negatively regulating miR-155-5p, thereby reducing ROS generation. Conclusions In conclusion, our results suggest that aFGF inhibits ROS-induced epithelial–mesenchymal transdifferentiation in diabetic vascular endothelial cells via the miR-155-5p/SIRT1/Nrf2/HO-1 axis, thereby promoting wound healing.

中文翻译：

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酸性成纤维细胞生长因子通过 miR-155-5p/SIRT1/Nrf2/HO-1 通路抑制活性氧诱导的血管内皮细胞上皮-间质转分化，促进糖尿病小鼠伤口愈合


背景 糖尿病慢性伤口是糖尿病最常见和最严重的并发症之一，与显着的发病率和死亡率相关。内皮间质转化（EndMT）是一种特定的病理状态，其中内皮细胞响应各种刺激（例如高葡萄糖水平和高氧化应激）而转化为间质细胞。酸性成纤维细胞生长因子（aFGF）是成纤维细胞生长因子家族的成员，具有很强的抗氧化特性，可以促进间充质干细胞分化为血管生成细胞。因此，我们研究了aFGF在糖尿病伤口EndMT中的作用并分析了其潜在机制。方法采用糖尿病小鼠模型验证aFGF对伤口愈合的影响，并体外考察高糖环境下aFGF对血管内皮细胞的影响。我们通过荧光素酶报告基因检测检测了高葡萄糖环境中 miR-155-5p 的表达以及 miR-155 下游靶基因 SIRT1。结果 aFGF 促进 2 型糖尿病小鼠模型的伤口闭合和新血管形成。在体外，aFGF 抑制血管内皮细胞中总活性氧和线粒体活性氧 (ROS) 的产生，并减轻高血糖环境下的上皮间质转分化。从机制上讲，aFGF通过负向调节miR-155-5p来促进SIRT1及其下游靶标Nrf2和HO-1的表达，从而减少ROS的产生。结论 总之，我们的结果表明，aFGF 通过 miR-155-5p/SIRT1/Nrf2/HO-1 轴抑制糖尿病血管内皮细胞中 ROS 诱导的上皮间质转分化，从而促进伤口愈合。