Aims Long non-coding RNA (LncRNA) small nucleolar RNA host gene 18 (SNHG18) has been widely implicated in cancers. However, little is known about its functional involvement in vascular diseases. Herein, we attempted to explore a role for SNHG18 in modulating vascular smooth muscle cell (VSMC) contractile phenotype and injury-induced neointima formation. Methods and Results Analysis of single cell RNA sequencing and transcriptomic datasets showed decreased levels of SNHG18 in injured and atherosclerotic murine and human arteries, which is positively associated with VSMC contractile genes. SNHG18 was upregulated in VSMCs by TGFβ1 through transcription factors Sp1 and SMAD3. SNHG18 gene gain/loss-of-function studies revealed that VSMC contractile phenotype was positively regulated by SNHG18. Mechanistic studies showed that SNHG18 promotes a contractile VSMC phenotype by up-regulating miR-22-3p. SNHG18 up-regulates miR-22 biogenesis and miR-22-3p production by competitive binding with the A-to-I RNA editing enzyme, adenosine deaminase acting on RNA-2 (ADAR2). Surprisingly, we observed that ADAR2 inhibited miR-22 biogenesis not through increasing A-to-I editing within primary miR-22, but by interfering the binding of microprocessor complex subunit DGCR8 to primary miR-22. Importantly, perivascular SNHG18 overexpression in the injured vessels dramatically up-regulated the expression levels of miR-22-3p and VSMC contractile genes, and prevented injury-induced neointimal hyperplasia. Such modulatory effects were reverted by miR-22-3p inhibition in the injured arteries. Finally, we observed a similar regulator role for SNHG18 in human VSMCs, and a decreased expression level of both SNHG18 and miR-22-3p in diseased human arteries; and we found that the expression level of SNHG18 was positively associated with that of miR-22-3p in both healthy and diseased human arteries. Conclusion We demonstrate that SNHG18 is a novel regulator in governing VSMC contractile phenotype and preventing injury-induced neointimal hyperplasia. Our findings have important implications for therapeutic targeting snhg18/miR-22-3p signalling in vascular diseases.

中文翻译：

---

SNHG18 控制血管平滑肌细胞收缩表型和新生内膜增生

目的 长非编码 RNA (LncRNA) 小核仁 RNA 宿主基因 18 (SNHG18) 与癌症广泛相关。然而，人们对其在血管疾病中的功能参与知之甚少。在此，我们试图探索 SNHG18 在调节血管平滑肌细胞 (VSMC) 收缩表型和损伤诱导的新内膜形成中的作用。方法和结果 单细胞 RNA 测序和转录组数据集的分析显示，受伤和动脉粥样硬化的小鼠和人类动脉中 SNHG18 水平降低，这与 VSMC 收缩基因呈正相关。 TGFβ1 通过转录因子 Sp1 和 SMAD3 在 VSMC 中上调 SNHG18。 SNHG18 基因获得/功能丧失研究表明，VSMC 收缩表型受到 SNHG18 的正向调节。机制研究表明，SNHG18 通过上调 miR-22-3p 促进收缩性 VSMC 表型。 SNHG18 通过与 A-to-I RNA 编辑酶、作用于 RNA-2 (ADAR2) 的腺苷脱氨酶竞争性结合，上调 miR-22 生物发生和 miR-22-3p 产生。令人惊讶的是，我们观察到 ADAR2 抑制 miR-22 生物合成不是通过增加初级 miR-22 内的 A-to-I 编辑，而是通过干扰微处理器复合物亚基 DGCR8 与初级 miR-22 的结合。重要的是，受损血管中血管周围 SNHG18 过度表达显着上调 miR-22-3p 和 VSMC 收缩基因的表达水平，并防止损伤诱导的新内膜增生。受损动脉中的 miR-22-3p 抑制可恢复这种调节作用。最后，我们观察到 SNHG18 在人类 VSMC 中具有类似的调节作用，并且在患病人类动脉中 SNHG18 和 miR-22-3p 的表达水平均降低；我们发现，在健康和患病的人类动脉中，SNHG18 的表达水平与 miR-22-3p 的表达水平呈正相关。结论 我们证明 SNHG18 是控制 VSMC 收缩表型和预防损伤引起的内膜增生的新型调节剂。我们的研究结果对于血管疾病中 snhg18/miR-22-3p 信号传导的治疗具有重要意义。