Department of Cardiology, Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Road, Guiyang 550004, Guizhou Province, China.
Department of Pulmonary and Critical Care Medicines, Zhuhai People's Hospital (Zhuhai Hospital affiliated with Jinan University), Zhuhai 519000, China.
Life Sci. 2022 Jan 1;288:119092. doi: 10.1016/j.lfs.2021.119092. Epub 2021 Mar 16.
Phenotypic switching of vascular smooth muscle cells (VSMCs) is essential for the formation of abdominal aortic aneurysms (AAAs). MicroRNA-23b (miR-23b) has recently been shown to play a vital role in maintaining the VSMC contractile phenotype; however, little is known about the role of miR-23b in the formation of AAAs. Here, we investigated whether miR-23b prevents AAA formation by inhibiting VSMC phenotypic switching.
We administered angiotensin II (Ang II, 1000 ng/kg/min) or vehicle to 10-12-week-old male apolipoprotein E knockout (ApoE) or C57BL/6J mice via subcutaneous osmotic minipumps for 4 weeks.
The expression of miR-23b was significantly reduced in the aorta during the early onset of AAA in angiotensin II-treated ApoE mice and in human AAA samples. In vitro experiments showed that the suppression of SMC contractile marker gene expression induced by Ang II was accelerated by miR-23b inhibitors but inhibited by mimics. In vivo studies revealed that miR-23b deficiency in Ang II-treated C57BL/6J mice aggravated the formation of AAAs in these mice compared with control mice; the opposite results were observed in miR-23b-overexpressing mice. Mechanistically, miR-23b knockdown significantly increased the expression of the transcription factor forkhead box O4 (FoxO4) during VSMC phenotypic switching induced by Ang II. In addition, a luciferase reporter assay showed that FoxO4 is a target of miR-23b in VSMCs.
Our study revealed a pivotal role for miR-23b in protecting against aortic aneurysm formation by maintaining the VSMC contractile phenotype.
血管平滑肌细胞（VSMCs）的表型转换对于腹主动脉瘤（AAA）的形成至关重要。最近的研究表明，microRNA-23b（miR-23b）在维持 VSMC 收缩表型方面发挥着重要作用；然而，miR-23b 在 AAA 形成中的作用知之甚少。在这里，我们研究了 miR-23b 是否通过抑制 VSMC 表型转换来预防 AAA 的形成。
我们通过皮下渗透微型泵向 10-12 周龄的载脂蛋白 E 敲除（ApoE）或 C57BL/6J 雄性小鼠给予血管紧张素 II（Ang II，1000ng/kg/min）或载体，持续 4 周。
在 Ang II 处理的 ApoE 小鼠和人类 AAA 样本中，AAA 早期主动脉中 miR-23b 的表达显著降低。体外实验表明，Ang II 诱导的 SMC 收缩标志物基因表达的抑制作用被 miR-23b 抑制剂加速，但被模拟物抑制。体内研究表明，与对照小鼠相比，Ang II 处理的 C57BL/6J 小鼠中 miR-23b 缺失加剧了这些小鼠的 AAA 形成；在 miR-23b 过表达的小鼠中观察到相反的结果。机制上，miR-23b 敲低在 Ang II 诱导的 VSMC 表型转换过程中显著增加了转录因子叉头框 O4（FoxO4）的表达。此外，荧光素酶报告基因测定表明 FoxO4 是 VSMCs 中 miR-23b 的靶标。
我们的研究揭示了 miR-23b 通过维持 VSMC 收缩表型在保护主动脉免受动脉瘤形成中的关键作用。
