Enhancement of glycolysis-dependent DNA repair regulated by FOXO1 knockdown via PFKFB3 attenuates hyperglycemia-induced endothelial oxidative stress injury.
Enhancement of glycolysis-dependent DNA repair regulated by FOXO1 knockdown via PFKFB3 attenuates hyperglycemia-induced endothelial oxidative stress injury.
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DOI：
10.1016/j.redox.2022.102589
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发表时间：
2023-02
期刊：
影响因子：
11.4
通讯作者：
Wei, Fang
中科院分区：
文献类型：
--
作者：
Sun, Dandan;Chen, Shimei;Li, Shenping;Wang, Ning;Zhang, Shuchang;Xu, Li;Zhu, Shaopin;Li, Huiming;Gu, Qing;Xu, Xun;Wei, Fang
氧化应激诱导的DNA损伤的积累是糖尿病血管并发症中内皮细胞丢失的重要致病因素，但目前尚不清楚糖代谢异常是否导致DNA修复缺陷，以及高血糖诱导的内皮氧化应激损伤。在这里，我们证明了Foxo1基因敲除减轻了糖尿病相关的视网膜DNA损伤和血管功能障碍。在机制上，FOXO1基因敲除通过促进氧化应激损伤的MRN(Mre11-Rad50-NBS1 Complex)-ATM通路介导的DNA修复，避免了高糖环境下内皮细胞持续的DNA损伤和细胞衰老。此外，FOXO1基因敲除通过恢复高糖下的糖酵解能力而介导了强大的DNA修复。在这个过程中，关键的糖酵解酶PFKFB3被激活，除了对糖酵解的促进作用外，还直接参与了DNA修复。在基因毒性应激下，PFKFB3通过与MRN-ATM途径相互作用，重新定位到氧化应激诱导的DNA损伤部位，促进DNA修复。我们的研究表明，糖尿病内皮细胞存在糖酵解依赖的DNA修复缺陷，并参与了高血糖诱导的血管功能障碍，这可能为糖尿病血管并发症提供新的治疗靶点。
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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影响因子：
29
作者：
Crespo-Garcia, Sergio;Tsuruda, Pamela R.;Sapieha, Przemyslaw
通讯作者：
Sapieha, Przemyslaw
影响因子：
64.5
作者：
De Bock, Katrien;Georgiadou, Maria;Carmeliet, Peter
通讯作者：
Carmeliet, Peter
影响因子：
5.9
作者：
Cargill KR;Stewart CA;Park EM;Ramkumar K;Gay CM;Cardnell RJ;Wang Q;Diao L;Shen L;Fan YH;Chan WK;Lorenzi PL;Oliver TG;Wang J;Byers LA
通讯作者：
Byers LA
影响因子：
56.9
作者：
Huang, Haojie;Regan, Kevin M.;Tindall, Donald J.
通讯作者：
Tindall, Donald J.
衰老中的细胞衰老：从机制到治疗机会。
DOI：
10.1038/s41580-020-00314-w
发表时间：
2021-03
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Di Micco R;Krizhanovsky V;Baker D;d'Adda di Fagagna F
通讯作者：
d'Adda di Fagagna F