circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating
Peng Kong1, Chang-Lin Li1, Yong-Qing Dou2
1Key Laboratory of Medical Biotechnology of Hebei Province, Key Laboratory of Neural and Vascular Biology of Ministry of Education, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei Medical University, Shijiazhuang, China.
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.
Insights
Circular RNA Sirt1 (circ-Sirt1) inhibits vascular smooth muscle cell senescence and inflammation. Targeting circ-Sirt1 may offer a new strategy for treating age-related vascular diseases.
Area of Science:
- Vascular Biology
- Molecular Biology
- Aging Research
Background:
- Vascular smooth muscle cell (VSMC) senescence drives neointimal formation.
- circ-Sirt1 suppresses VSMC inflammation and neointimal formation.
- The role of circ-Sirt1 in VSMC senescence during neointimal hyperplasia is unclear.
Purpose of the Study:
- To investigate the effect of circ-Sirt1 on VSMC senescence.
- To elucidate the mechanism by which circ-Sirt1 regulates VSMC senescence.
- To explore circ-Sirt1 as a therapeutic target for vascular diseases.
Main Methods:
- Assessed circ-Sirt1 expression in young and aged human and mouse arteries.
- Overexpressed circ-Sirt1 in vitro and in vivo models.
- Investigated circ-Sirt1 interaction with p53 and SIRT1.
- Analyzed p53 transcriptional and post-translational regulation.
Main Results:
- circ-Sirt1 expression decreases in aged arteries and neointima.
- circ-Sirt1 overexpression delays Ang II-induced VSMC senescence and ameliorates neointimal hyperplasia.
- circ-Sirt1 inhibits p53 activity by blocking nuclear translocation and promoting deacetylation via SIRT1.
Conclusions:
- circ-Sirt1 acts as a novel repressor of p53 in response to senescence stimuli.
- circ-Sirt1 plays a protective role against VSMC senescence and neointimal hyperplasia.
- Targeting circ-Sirt1 presents a potential therapeutic strategy for aging-related vascular diseases.
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