Enhancement of glycolysis-dependent DNA repair regulated by FOXO1 knockdown via PFKFB3 attenuates hyperglycemia-induced endothelial oxidative stress injury

Redox Biol. 2023 Feb:59:102589. doi: 10.1016/j.redox.2022.102589. Epub 2022 Dec 25.

Abstract

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.

Keywords: DNA damage; DNA repair; Diabetes; Endothelial cell; Glycolysis; Oxidative stress.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle Proteins / metabolism
  • DNA Damage
  • DNA Repair
  • Diabetic Angiopathies* / metabolism
  • Endothelial Cells / metabolism
  • Forkhead Box Protein O1 / metabolism
  • Glucose / metabolism
  • Glycolysis
  • Humans
  • Hyperglycemia* / genetics
  • Hyperglycemia* / metabolism
  • Oxidative Stress
  • Phosphofructokinase-2 / genetics
  • Phosphofructokinase-2 / metabolism

Substances

  • Cell Cycle Proteins
  • Glucose
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • PFKFB3 protein, human
  • Phosphofructokinase-2