Liraglutide attenuates high glucose-induced endothelial cell senescence and dysfunction via SIRT1-mediated deacetylation of p53/p65.

Endothelial aging is a critical pathogenic factor in various cardiovascular and metabolic disorders. Liraglutide (LIR), a glucagon-like peptide-1 receptor (GLP-1R) agonist used clinically to treat diabetes, controls blood sugar levels, and alleviates vascular stress, thereby protecting blood vessels. However, the mechanism by which it improves vascular aging remains to be elucidated. In this study, human umbilical vein endothelial cells were subjected to 30 mM glucose induction, followed by the addition of 1 μM LIR for 72 h. The findings indicated that LIR mitigated high glucose-induced endothelial cell senescence and downregulated the expression of markers linked to senescence, reactive oxygen species (ROS), and oxidative stress (p < 0.05). Additionally, it upregulated the expression of antioxidant markers and promoted angiogenesis and migration (p < 0.05). Western blot analysis of protein changes revealed that the therapeutic effects of LIR depend on SIRT1 and the acetylation of p53 and p65. Through SIRT1 overexpression and knockdown, we determined that SIRT1 regulates the acetylation of p53 and p65. Notably, the absence of SIRT1 diminished the therapeutic effects of LIR, whereas its overexpression enhanced these effects. Our findings suggest that high-glucose-induced endothelial cell aging and dysfunction may be involved in the pathogenesis of diabetic cardiovascular diseases (CVD). LIR treatment of high-glucose-induced vascular aging relies on the SIRT1-p53/p65 signaling axis. This study elucidates the mechanisms by which LIR ameliorates vascular aging and proposes a novel approach to mitigate vascular aging in elderly patients with diabetes.