circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation.
circ-Sirt1 Decelerates Senescence by Inhibiting p53 Activation in Vascular Smooth Muscle Cells, Ameliorating Neointima Formation.
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circ-Sirt1 通过抑制血管平滑肌细胞中 p53 的激活来减缓衰老，改善新内膜形成
DOI：
10.3389/fcvm.2021.724592
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发表时间：
2021
影响因子：
3.6
通讯作者：
Han M
中科院分区：
文献类型：
--
作者：
Kong P;Li CL;Dou YQ;Cao L;Zhang XY;Zhang WD;Bi ZQ;Peng ZY;Yan AQ;Han M
血管平滑肌细胞（VSMC）衰老是新内膜形成的主要驱动因素。我们已经证明源自 SIRT1 基因的 circ-Sirt1 可以抑制 VSMC 炎症和新内膜形成。然而，circ-Sirt1抑制炎症对新生内膜增生期间VSMC衰老的影响仍有待阐明。在这里，我们发现 circ-Sirt1 在年轻和健康的动脉中高度表达，而在人类和小鼠的衰老动脉和新内膜中表达减少。 circ-Sirt1 的过度表达在体外延迟了 Ang II 诱导的 VSMC 衰老，并在体内改善了新生内膜增生。从机械角度来看，circ-Sirt1 在转录和翻译后调节水平上抑制 p53 活性。具体而言，circ-Sirt1一方面与p53相互作用并保持p53以阻止其核转位，另一方面促进SIRT1介导的p53脱乙酰化和失活。总之，我们的数据表明，circ-Sirt1 是一种新型 p53 阻遏蛋白，可响应衰老诱导刺激，并且靶向 circ-Sirt1 可能是改善衰老相关血管疾病的一种有前途的方法。
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.