Vascular complications of diabetes are a serious challenge in clinical practice, and effective treatments are an unmet clinical need. Acidic fibroblast growth factor (aFGF) has potent anti-oxidative properties and therefore has become a research focus for the treatment of diabetic vascular complications. However, the specific mechanisms by which aFGF regulates these processes remain unclear. The purpose of this study was to investigate whether aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress. We found that aFGF markedly decreased mitochondrial superoxide generation in both db/db mice and endothelial cells incubated with high glucose (30 mM) plus palmitic acid (PA, 0.1 mM), and restored diabetes-impaired Wnt/β-catenin signaling. Pretreatment with the Wnt/β-catenin signaling inhibitors IWR-1-endo (IWR) and ICG-001 abolished aFGF-mediated attenuation of mitochondrial superoxide generation and endothelial protection. Furthermore, the effects of aFGF on endothelial protection under diabetic conditions were suppressed by c-Myc knockdown. Mechanistically, c-Myc knockdown triggered mitochondrial superoxide generation, which was related to decreased expression and subsequent impaired mitochondrial localization of hexokinase 2 (HXK2). The role of HXK2 in aFGF-mediated attenuation of mitochondrial superoxide levels and EC protection was further confirmed by si-Hxk2 and a cell-permeable form of hexokinase II VDAC binding domain (HXK2VBD) peptide, which inhibits mitochondrial localization of HXK2. Taken together, these findings suggest that the endothelial protective effect of aFGF under diabetic conditions could be partly attributed to its role in suppressing mitochondrial superoxide generation via HXK2, which is mediated by the Wnt/β-catenin/c-Myc axis.

糖尿病的血管并发症是临床实践中的严峻挑战，有效的治疗是临床未满足的需求。酸性成纤维细胞生长因子（aFGF）具有强大的抗氧化特性，因此已成为治疗糖尿病血管并发症的研究热点。然而，aFGF 调节这些过程的具体机制仍不清楚。本研究的目的是研究 aFGF 是否通过抑制线粒体氧化应激来缓解糖尿病内皮功能障碍。我们发现，aFGF 显着降低了 db/db 小鼠和用高葡萄糖（30 mM）加棕榈酸（PA，0.1 mM）孵育的内皮细胞中线粒体超氧化物的产生，并恢复了糖尿病受损的 Wnt/β-连环蛋白信号传导。用 Wnt/β-连环蛋白信号通路抑制剂 IWR-1-endo (IWR) 和 ICG-001 预处理消除了 aFGF 介导的线粒体超氧化物生成和内皮保护作用的减弱。此外，c-Myc 敲低抑制了 aFGF 在糖尿病条件下对内皮保护的影响。从机制上讲，c-Myc 敲低触发了线粒体超氧化物的产生，这与己糖激酶 2 (HXK2) 的表达降低和随后的线粒体定位受损有关。HXK2 在 aFGF 介导的线粒体超氧化物水平衰减和 EC 保护中的作用被 si- 进一步证实。c-Myc 敲低抑制了 aFGF 在糖尿病条件下对内皮保护的影响。从机制上讲，c-Myc 敲低触发了线粒体超氧化物的产生，这与己糖激酶 2 (HXK2) 的表达降低和随后的线粒体定位受损有关。HXK2 在 aFGF 介导的线粒体超氧化物水平衰减和 EC 保护中的作用被 si- 进一步证实。c-Myc 敲低抑制了 aFGF 在糖尿病条件下对内皮保护的影响。从机制上讲，c-Myc 敲低触发了线粒体超氧化物的产生，这与己糖激酶 2 (HXK2) 的表达降低和随后的线粒体定位受损有关。HXK2 在 aFGF 介导的线粒体超氧化物水平衰减和 EC 保护中的作用被 si- 进一步证实。Hxk2和细胞渗透形式的己糖激酶 II VDAC 结合域 (HXK2VBD) 肽，可抑制 HXK2 的线粒体定位。总之，这些发现表明，aFGF 在糖尿病条件下的内皮保护作用可能部分归因于其通过 HXK2 抑制线粒体超氧化物生成的作用，HXK2 由 Wnt/β-catenin/c-Myc 轴介导。