William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, UK.
Department of Otorhinolaryngology, Third Affiliated Hospital of Anhui Medical University, No. 390, Huaihe Road, LuYang District, Hefei, Anhui, 230061, PR China.
Cardiovasc Res. 2024 May 29;120(7):796-810. doi: 10.1093/cvr/cvae055.
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.
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 with 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.
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.
长链非编码 RNA（LncRNA）小核仁 RNA 宿主基因 18（SNHG18）已广泛涉及癌症。然而，其在血管疾病中的功能作用知之甚少。在此，我们试图探讨 SNHG18 在调节血管平滑肌细胞（VSMC）收缩表型和损伤诱导的新生内膜形成中的作用。
单细胞 RNA 测序和转录组数据集的分析表明，损伤和动脉粥样硬化的小鼠和人类动脉中 SNHG18 水平降低，与 VSMC 收缩基因呈正相关。TGFβ1 通过转录因子 Sp1 和 SMAD3 上调 VSMCs 中的 SNHG18。SNHG18 基因的增益/缺失功能研究表明，SNHG18 正向调节 VSMC 收缩表型。机制研究表明，SNHG18 通过上调 miR-22-3p 促进收缩型 VSMC 表型。SNHG18 通过与 A 到 I RNA 编辑酶腺苷脱氨酶作用于 RNA-2（ADAR2）竞争性结合，促进 miR-22 的生物发生和 miR-22-3p 的产生。令人惊讶的是，我们观察到 ADAR2 抑制 miR-22 生物发生不是通过增加初级 miR-22 内的 A 到 I 编辑，而是通过干扰 microprocessor 复合物亚基 DGCR8 与初级 miR-22 的结合。重要的是，损伤血管周围 SNHG18 的过表达显著上调了 miR-22-3p 和 VSMC 收缩基因的表达水平，并防止了损伤诱导的新生内膜增生。在损伤的动脉中，miR-22-3p 的抑制逆转了这种调节作用。最后，我们在人类 VSMCs 中观察到 SNHG18 具有类似的调节作用，在疾病相关的人类动脉中 SNHG18 和 miR-22-3p 的表达水平均降低；并且我们发现，在健康和疾病相关的人类动脉中，SNHG18 的表达水平与 miR-22-3p 的表达水平呈正相关。
我们证明 SNHG18 是一种新的调节因子，可调节 VSMC 收缩表型并防止损伤诱导的新生内膜增生。我们的研究结果对于血管疾病中靶向 SNHG18/miR-22-3p 信号的治疗具有重要意义。
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