Circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation.

Peng Kong,Li Cao,Yong-Qing Dou,An-Qi Yan,Ze-Qi Bi,Zu-Yi Peng,Mei Han,Xiao-Yun Zhang,Wen-Di Zhang,Chang-Lin Li

doi:10.3389/fcvm.2021.724592

Abstract

Vascular smooth muscle cell (VSMC) senescence is a major driver of neointimal formation. We have demonstrated that circ-Sirt1 derived from the SIRT1 gene suppressed VSMC inflammation and neointimal formation. However, the effect of circ-Sirt1 inhibiting inflammation on VSMC senescence during neointimal hyperplasia remains to be elucidated. Here, we showed that circ-Sirt1 was highly expressed in young and healthy arteries, which was decreased in aged arteries and neointima of humans and mice. Overexpression of circ-Sirt1 delayed Ang II-induced VSMC senescence in vitro and ameliorated neointimal hyperplasia in vivo. Mechanically, circ-Sirt1 inhibited p53 activity at the levels of transcription and post-translation modulation. In detail, circ-Sirt1, on the one hand, interacted with and held p53 to block its nuclear translocation, and on the other hand, promoted SIRT1-mediated p53 deacetylation and inactivation. In conclusion, our data suggest that circ-Sirt1 is a novel p53 repressor in response senescence-inducing stimuli, and targeting circ-Sirt1 may be a promising approach to ameliorating aging-related vascular disease.

Highlights

Aging is a biological process caused by the accumulation of senescent cells that are defined as an irreversible loss of proliferation potential [1]
We showed that the expression of circ-Sirt1 was decreased in the arteries of aged mice compared with young group (Figure 1A), accompanied with increased senescence markers p53 and p21 levels (Figure 1B)
Most of these cells were smooth muscle marker ACTA2-positive Vascular smooth muscle cell (VSMC), which mainly located in the neointima region and rarely in the media (Figure 1D). Quantitative Reverse Transcription-PCR (qRT-PCR) and RNA in situ hybridization verified that circ-Sirt1 was decreased in neointimal formation (Figures 1F,G), indicating that VSMC senescence may be correlated with reduced circ-Sirt1 production

Summary

Introduction

Aging is a biological process caused by the accumulation of senescent cells that are defined as an irreversible loss of proliferation potential [1]. It has been known that VSMC senescence promotes neointimal formation via increase in migration, oxidative stress, inflammation and collagen deposition in the intima in response to vascular injury [3, 4]. Several studies have shown evidence for the contribution of senescent cells to the development of vascular proliferative diseases, the mechanism by which aging exaggerates neointima formation after vascular injury has, so far, remained elusive. Our previous study demonstrated that circ-Sirt Inhibits Senescence circ-Sirt derived from the SIRT1 gene suppressed vascular inflammation and neointimal formation by direct interaction with NF-κB p65 and promoting expression of SIRT1, an NAD+dependent deacetylase, through competitive binding to miR132/212 [8]. The effect of circ-Sirt inhibiting vascular inflammation on cellular senescence during neointimal hyperplasia remains to be elucidated

Methods

Results

Conclusion