FBXW7 alleviates hyperglycemia-induced endothelial oxidative stress injury via ROS and PARP inhibition

Area of Science:

• Biomedical research
• Molecular biology
• Vascular biology

Background:

• Diabetic retinopathy and vascular complications stem from poor glycemic control.
• Hyperglycemia triggers oxidative stress, DNA damage, and PARP overactivation, impairing endothelial cells.
• FBXW7 regulates mitochondrial homeostasis and PGC-1α stability.

Purpose of the Study:

• To investigate FBXW7's role in repairing endothelial oxidative stress injuries under hyperglycemia.
• To elucidate the mechanism by which FBXW7 mitigates diabetic vascular damage.

Main Methods:

• Investigated FBXW7's effect on DNA double-strand break repair pathways (homologous recombination and non-homologous end joining).
• Assessed FBXW7's impact on PARP activation, expression, and activity in human endothelial cells and diabetic rat retinas.
• Evaluated FBXW7's influence on NAD+ levels, mitochondrial function, and superoxide production.
• Examined FBXW7's efficacy in reversing oxidative injury and vascular leakage in a diabetic rat model.

Main Results:

• FBXW7 enhanced DNA double-strand break repair, suppressing PARP hyperactivation and its downstream effects.
• FBXW7 downregulated PARP expression and activity in endothelial cells and retinas.
• FBXW7 restored NAD+ levels, improved mitochondrial function, and reduced superoxide production.
• FBXW7 treatment reversed hyperglycemia-induced oxidative injury and vascular leakage in diabetic rat retinas.

Conclusions:

• FBXW7 plays a critical role in repairing endothelial oxidative stress injuries under hyperglycemic conditions.
• FBXW7-mediated DNA repair offers a novel therapeutic strategy for inhibiting PARP activation, surpassing traditional PARP inhibitors for diabetic vascular complications.
• FBXW7 demonstrates potential as a future treatment for diabetic retinopathy and related vascular diseases by restoring cellular homeostasis and reducing oxidative damage.