Mei Xiaohan, Cui Xiao-Bing, Li Yiran, Chen Shi-You
Departments of Surgery (X.M., X.-B.C., S.-Y.C.), University of Missouri School of Medicine, Columbia.
Department of Physiology and Pharmacology (X.M., S.-Y.C.), University of Georgia, Athens.
Arterioscler Thromb Vasc Biol. 2021 Dec;41(12):2961-2973. doi: 10.1161/ATVBAHA.121.316911. Epub 2021 Oct 21.
Vascular smooth muscle cell (SMC) proliferation contributes to neointima formation following vascular injury. Circular RNA-a novel type of noncoding RNA with closed-loop structure-exhibits cell- and tissue-specific expression patterns. However, the role of circular RNA in SMC proliferation and neointima formation is largely unknown. The objective of this study is to investigate the role and mechanism of circSOD2 in SMC proliferation and neointima formation. Approach and Results: Circular RNA profiling of human aortic SMCs revealed that PDGF (platelet-derived growth factor)-BB up- and downregulated numerous circular RNAs. Among them, circSOD2, derived from back-splicing event of SOD2 (superoxide dismutase 2), was significantly enriched. Knockdown of circSOD2 by short hairpin RNA blocked PDGF-BB-induced SMC proliferation. Inversely, circSOD2 ectopic expression promoted SMC proliferation. Mechanistically, circSOD2 acted as a sponge for miR-206, leading to upregulation of NOTCH3 (notch receptor 3) and NOTCH3 signaling, which regulates cyclin D1 and CDK (cyclin-dependent kinase) 4/6. In vivo studies showed that circSOD2 was induced in neointima SMCs in balloon-injured rat carotid arteries. Importantly, knockdown of circSOD2 attenuated injury-induced neointima formation along with decreased neointimal SMC proliferation.
CircSOD2 is a novel regulator mediating SMC proliferation and neointima formation following vascular injury. Therefore, circSOD2 could be a potential therapeutic target for inhibiting the development of proliferative vascular diseases.
血管平滑肌细胞（SMC）增殖会导致血管损伤后新生内膜形成。环状RNA——一种具有闭环结构的新型非编码RNA——呈现细胞和组织特异性表达模式。然而，环状RNA在SMC增殖和新生内膜形成中的作用很大程度上尚不清楚。本研究的目的是探讨circSOD2在SMC增殖和新生内膜形成中的作用及机制。方法与结果：对人主动脉SMC进行环状RNA分析发现，血小板衍生生长因子（PDGF）-BB上调和下调了许多环状RNA。其中，源自超氧化物歧化酶2（SOD2）反向剪接事件的circSOD2显著富集。用短发夹RNA敲低circSOD2可阻断PDGF-BB诱导的SMC增殖。相反，circSOD2异位表达促进SMC增殖。机制上，circSOD2作为miR-206的海绵，导致Notch受体3（NOTCH3）和NOTCH3信号上调，后者调节细胞周期蛋白D1和细胞周期蛋白依赖性激酶（CDK）4/6。体内研究表明，在球囊损伤的大鼠颈动脉新生内膜SMC中circSOD2被诱导。重要的是，敲低circSOD2可减轻损伤诱导的新生内膜形成，并减少新生内膜SMC增殖。
CircSOD2是介导血管损伤后SMC增殖和新生内膜形成的新型调节因子。因此，circSOD2可能是抑制增殖性血管疾病发展的潜在治疗靶点。
