环状 Sirt1 通过与血管平滑肌细胞中的 miR-132/212 序列特异性相互作用和增强 Sirt1 表达来控制 NF-κB 激活。

circ-Sirt1 controls NF-κB activation via sequence-specific interaction and enhancement of SIRT1 expression by binding to miR-132/212 in vascular smooth muscle cells.

机构信息

Department of Biochemistry and Molecular Biology, College of Basic Medicine, Key Laboratory of Medical Biotechnology of Hebei Province, Hebei Medical University, Shijiazhuang, China.

Department of Surgery, the Fourth Affiliated Hospital, Hebei Medical University, Shijiazhuang, China.

出版信息

Nucleic Acids Res. 2019 Apr 23;47(7):3580-3593. doi: 10.1093/nar/gkz141.

NF-κB-mediated inflammatory phenotypic switching of vascular smooth muscle cells (VSMCs) plays a central role in atherosclerosis and neointimal formation. However, little is known about the roles of circRNAs in the regulation of NF-κB signaling. Here, we identify the involvement of circ-Sirt1 that was one of transcripts of SIRT1 host gene in VSMC inflammatory response and neointimal hyperplasia. First, in the cytoplasm, circ-Sirt1 directly interacts with and sequesters NF-κB p65 from nuclear translocation induced by TNF-α in a sequence-dependent manner. The inhibitory complex of circ-Sirt1-NF-κB p65 is not dependent on IκBα. Second, circ-Sirt1 binds to miR-132/212 that interferes with SIRT1 mRNA, and facilitates the expression of host gene SIRT1. Increased SIRT1 results in deacetylation and inactivation of the nuclear NF-κB p65. These findings illustrate that circ-Sirt1 is a novel non-coding RNA regulator of VSMC phenotype.

NF-κB 介导的血管平滑肌细胞 (VSMC) 炎症表型转换在动脉粥样硬化和新生内膜形成中起核心作用。然而，关于 circRNAs 在 NF-κB 信号调节中的作用知之甚少。在这里，我们鉴定了 circ-Sirt1 的参与，circ-Sirt1 是 SIRT1 宿主基因的转录物之一，参与 VSMC 炎症反应和新生内膜增生。首先，在细胞质中，circ-Sirt1 以序列依赖性方式直接与 TNF-α诱导的 NF-κB p65 相互作用，并将其隔离，使其无法发生核易位。circ-Sirt1-NF-κB p65 的抑制复合物不依赖于 IκBα。其次，circ-Sirt1 结合 miR-132/212，干扰 SIRT1 mRNA，并促进宿主基因 SIRT1 的表达。增加的 SIRT1 导致核 NF-κB p65 的去乙酰化和失活。这些发现表明 circ-Sirt1 是 VSMC 表型的新型非编码 RNA 调节剂。