REDD1 knockdown ameliorates endothelial cell senescence through repressing TXNIP-mediated oxidative stress

Area of Science:

• Cardiovascular Biology
• Cellular Senescence
• Molecular Medicine

Background:

• Endothelial cell senescence, marked by reactive oxygen species (ROS) and inflammation, drives atherosclerosis (AS).
• Regulated in development and DNA damage response 1 (REDD1), a stress-response protein, influences age-related diseases, but its role in endothelial cell senescence is unknown.

Purpose of the Study:

• To investigate the role of REDD1 in endothelial cell senescence and its contribution to atherosclerosis.
• To elucidate the mechanism by which REDD1 regulates ROS production in senescent endothelial cells.

Main Methods:

• Bioinformatic screening identified REDD1 as a differentially expressed senescence-related gene in AS.
• AS and aging mouse models, D-galactose (DG)-induced senescent endothelial cells were established.
• REDD1 expression was analyzed; siRNA and N-Acetylcysteine (NAC) treatments were applied to assess REDD1's function and the ROS-REDD1 feedback loop, including TXNIP-REDD1 interaction.

Main Results:

• REDD1 expression was upregulated in AS plaques, senescent endothelial cells, and aging aortas.
• siRNA-mediated REDD1 inhibition ameliorated DG-induced endothelial cell senescence and reduced ROS accumulation.
• NAC treatment, an antioxidant, reduced ROS and also downregulated REDD1, suggesting a positive feedback loop between REDD1 and ROS in endothelial cell senescence.
• REDD1's regulation of ROS was linked to the TXNIP-REDD1 interaction.

Conclusions:

• REDD1 promotes endothelial cell senescence and oxidative stress, potentially via repressing TXNIP-mediated pathways.
• REDD1 plays a significant role in the progression of atherosclerosis.
• Targeting REDD1 may represent a novel therapeutic approach for atherosclerosis by mitigating endothelial cell senescence and oxidative stress.