期刊
REDOX BIOLOGY
卷 39, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.redox.2020.101811
关键词
aFGF; Diabetes; Endothelial dysfunction; Mitochondrial superoxide; HXK2
资金
- National Natural Science Foundation of China [81903235, 81870209, 81773346, 81770498, 82070507]
- Key Scientific Project of MOST, China [2017YFA0506000]
- Natural Science Foundation of Zhejiang Province [LQ18H020004, Y21H020057]
- Zhejiang Province Medical and Health Science Program [2019KY099, 2019RC054]
- Wenzhou Science and Technology Bureau Foundation [Y20180145, Y20190164]
The study showed that aFGF alleviates diabetic endothelial dysfunction by suppressing mitochondrial oxidative stress through the Wnt/beta-catenin/c-Myc axis and HXK2. The specific mechanisms by which aFGF regulates these processes remain unclear.
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/p-catenin signaling. Pretreatment with the Wnt/beta-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/beta-catenin/c-Myc axis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据