Mechanism of Resveratrol in Delaying Vascular Endothelial Cell Senescence Based on SRC-NF-κB Signaling Pathway

OBJECTIVE To investigate the mechanism of resveratrol in delaying vascular endothelial cell senescence.

METHODS Network pharmacology was used to screen potential anti-aging targets and signaling pathways of resveratrol, and molecular docking was performed on core targets. A cellular aging model of human aortic endothelial cells was established by hydrogen peroxide induction. After drug intervention, cell viability, senescence-associated β-galactosidase positive rate, and reactive oxygen species(ROS) levels, mRNA expression of inflammatory factors, and pathway-related protein expression were detected. Rescue experiments were conducted using the steroid receptor coactivator(SRC) inhibitor PP2 and the agonist tolimidone. An aging mouse model was induced by D-galactose to assess frailty phenotypes, mRNA expression of inflammatory factors in aortic tissue, and key protein expression.

RESULTS A total of 89 potential anti-aging targets of resveratrol were identified, which were significantly enriched in histone site-specific kinase activity, membrane raft signaling microdomains, and vascular stress- and inflammation-related pathways. Molecular docking showed good binding activity of resveratrol with core targets such as SRC, nuclear factor κB subunit 1(NFκB1), prostaglandin-endoperoxide synthase 2(PTGS2), and matrix metalloproteinase-9(MMP9). Cellular experiments showed that resveratrol increased cell viability, reduced senescence positive rate, ROS levels, and downregulated the protein expression of cyclin-dependent kinase inhibitor 1A(P21) and cyclin-dependent kinase inhibitor 2A(P16). It also decreased the mRNA expression of tumor necrosis factor-α, interleukin-1β, interleukin-6, and interleukin-17, while inhibiting SRC phosphorylation, NF-κB p65 nuclear translocation, and downstream PTGS2 and MMP9 expression. Rescue experiments confirmed that the SRC inhibitor enhanced the anti-aging effects of resveratrol, whereas the SRC agonist partially reversed its protective effects. Animal experiments showed that resveratrol improved frailty phenotypes in aging mice, reduced mRNA expression of inflammatory factors in aortic tissue, and inhibited the activation of the SRC-NF-κB pathway and the expression of P21 and P16 in aortic tissue.

CONCLUSION Resveratrol delays vascular endothelial cell senescence by inhibiting the SRC-NF-κB signaling pathway and reducing the inflammatory response.