Department of Interventional Radiology, Tongji Hospital of Tongji University, 389, Xincun Road, Shanghai, 200065, China.
BMC Mol Cell Biol. 2023 Jan 30;24(1):3. doi: 10.1186/s12860-022-00461-2.
Alterations in vascular smooth muscle cells (VSMCs) contribute to the pathogenesis of intracranial aneurysms (IAs). However, molecular mechanisms underlying these changes remain unknown. The present study aimed to characterize the molecular mechanisms underlying VSMC-mediated IAs.
Expression of the circular RNA circ-ATL1 and microRNA miR-455 was detected in IAs by RT-qPCR. Interactions between circ-ATL1, miR-455 and SIRT5 were examined by luciferase reporter analysis and RT-qPCR. The regulatory roles of circ-ATL1, miR-455 and SIRT5 in VSMC migration, proliferation and phenotypic modulation were also examined by CCK8, Transwell® migration and western blot assays.
Biochemical and bioinformatic techniques were used to demonstrate that circ-ATL1 and miR-455 participated in disparate biological processes relevant to aneurysm formation. Clinically, increased expression of circ-ATL1 and downregulated miR-455 expression were observed in IA patients compared with healthy subjects. Silencing of circ-ATL1 led to suppression of VSMC migration, proliferation and phenotypic modulation. Both SIRT5 and miR-455 were found to be downstream targets of circ-ATL1. SIRT5 upregulation or miR-455 inhibition reversed the inhibitory effects induced by circ-ATL1 silencing on VSMC proliferation, migration and phenotypic modulation. We found that VSMC phenotypic modulation by circ-ATL1 upregulation and miR-455 downregulation had a critical role in the development and formation of AIs. Specifically, circ-ATL1 downregulation reversed IA formation.
Our data provide the theoretical basis for future studies on potential clinical treatment and prevention of IAs.
血管平滑肌细胞（VSMCs）的改变导致颅内动脉瘤（IAs）的发病机制。然而，这些变化的分子机制尚不清楚。本研究旨在描述 VSMC 介导的 IAs 的分子机制。
通过 RT-qPCR 检测 IA 中 circ-ATL1 和 miR-455 的表达。通过荧光素酶报告分析和 RT-qPCR 检测 circ-ATL1、miR-455 和 SIRT5 之间的相互作用。通过 CCK8、Transwell®迁移和 Western blot 测定还检测了 circ-ATL1、miR-455 和 SIRT5 对 VSMC 迁移、增殖和表型调节的调节作用。
生化和生物信息学技术表明，circ-ATL1 和 miR-455 参与了与动脉瘤形成相关的不同生物学过程。临床研究表明，与健康受试者相比，IA 患者的 circ-ATL1 表达增加，miR-455 表达下调。沉默 circ-ATL1 导致 VSMC 迁移、增殖和表型调节受到抑制。SIRT5 和 miR-455 被发现是 circ-ATL1 的下游靶标。SIRT5 上调或 miR-455 抑制逆转了 circ-ATL1 沉默对 VSMC 增殖、迁移和表型调节的抑制作用。我们发现，circ-ATL1 上调和 miR-455 下调对 VSMC 表型调节在 AI 的发生和形成中起关键作用。具体来说，circ-ATL1 的下调逆转了 IA 的形成。
我们的数据为未来研究提供了理论依据，以潜在地治疗和预防 IAs。
