Capsaicin Receptor TRPV1 Delays Aortic Aging in Atherosclerotic Mice by Inhibiting the ISG15-p53 Pathway

Vascular aging constitutes a significant pathological basis for the aging of various organs and systems within the human body. This study employed a murine model of atherosclerosis (AS) and Transient Receptor Potential Vanilloid 1 (TRPV1)-deficient AS mice to ascertain whether TRPV1 exerts an influence on AS by modulating aortic aging. Furthermore, the study sought to expand upon the molecular mechanisms by which TRPV1 regulates aortic aging. TRPV1 expression was examined in aortic tissue of Apoe^-/- mice, and its expression level was significantly reduced in comparison with that of control mice. Apoe^-/-Trpv1^-/- mice were subjected to a high-fat diet, after which a significant increase in aortic sinus senescent cell area, senescence-associated secretory phenotypes (SASP) and expression of senescence-associated proteins was observed, accompanied by an increase in plaque area and instability. Transcriptome sequencing ascertained that the deletion of TRPV1 led to a substantial augmentation in the expression of ubiquitin-like protein 15 (ISG15) within the aortic tissue. It then demonstrated that TRPV1 deletion promotes ISG15-induced aortic senescence using Apoe^-/-Trpv1^-/- high-fat dietary mice, as well as cellular experiments. Studies utilising PPI analysis and in vitro cultured EA.hy926 cells have demonstrated that ISG15 promotes vascular endothelial cell senescence by facilitating the expression and phosphorylation of p53 and p21, and by impeding the phosphorylation of retinoblastoma (Rb). Aortic TRPV1 deficiency promotes aortic senescence by promoting upregulation of ISG15 expression, which in turn promotes p53 and p21 phosphorylation and inhibits Rb phosphorylation.