Premature endothelial senescence decreases the atheroprotective capacity of the arterial endothelium. Apolipoprotein C3 (ApoC3) delays the catabolism of triglyceride-rich particles and plays a critical role in atherosclerosis progression. FBXO31 is required for the intracellular response to DNA damage, which is a significant cause of cellular senescence. Sesamol is a natural antioxidant with cardiovascular-protective properties. In this study, we aimed to examine the effects of ApoC3-rich low-density lipoprotein (AC3RL) mediated via FBXO31 on endothelial cell (EC) senescence and its inhibition by sesamol. AC3RL and ApoC3-free low-density lipoproteins (LDL) (AC3(-)L) were isolated from the plasma LDL of patients with ischemic stroke. Human aortic endothelial cells (HAECs) treated with AC3RL induced EC senescence in a dose-dependent manner. AC3RL induced HAEC senescence via DNA damage. However, silencing FBXO31 attenuated AC3RL-induced DNA damage and reduced cellular senescence. Thus, FBXO31 may be a novel therapeutic target for endothelial senescence-related cardiovascular diseases. Moreover, the aortic arch of hamsters fed a high-fat diet with sesamol showed a substantial reduction in their atherosclerotic lesion size. In addition to confirming the role of AC3RL in aging and atherosclerosis, we also identified AC3RL as a potential therapeutic target that can be used to combat atherosclerosis and the onset of cardiovascular disease in humans.
