氧化应激
基因敲除
DNA修复
DNA损伤
福克斯O1
糖酵解
细胞生物学
生物
癌症研究
DNA
信号转导
内分泌学
生物化学
新陈代谢
基因
蛋白激酶B
作者
Dandan Sun,Shimei Chen,Shenping Li,Ning Wang,Shuchang Zhang,Li Xu,Shaopin Zhu,Huiming Li,Qing Gu,Xun Xu,Fang Wei
出处
期刊:Redox biology
[Elsevier]
日期:2023-02-01
卷期号:59: 102589-102589
被引量:9
标识
DOI:10.1016/j.redox.2022.102589
摘要
The accumulation of DNA damage induced by oxidative stress is a crucial pathogenic factor of endothelial loss in diabetic vascular complications, but it is still unknown whether aberrant glucose metabolism leads to defective DNA repair and accounts for hyperglycemia-induced endothelial oxidative stress injury. Here, we showed that Foxo1 knockdown alleviated diabetes-associated retinal DNA damage and vascular dysfunction. Mechanistically, FOXO1 knockdown avoided persistent DNA damage and cellular senescence under high glucose in endothelial cells by promoting DNA repair mediated by the MRN (MRE11-RAD50-NBS1 complex)-ATM pathway in response to oxidative stress injury. Moreover, FOXO1 knockdown mediated robust DNA repair by restoring glycolysis capacity under high glucose. During this process, the key glycolytic enzyme PFKFB3 was stimulated and, in addition to its promoting effect on glycolysis, directly participated in DNA repair. Under genotoxic stress, PFKFB3 relocated into oxidative stress-induced DNA damage sites and promoted DNA repair by interaction with the MRN-ATM pathway. Our study proposed that defective glycolysis-dependent DNA repair is present in diabetic endothelial cells and contributes to hyperglycemia-induced vascular dysfunction, which could provide novel therapeutic targets for diabetic vascular complications.
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