MicroRNA-23b prevents aortic aneurysm formation by inhibiting smooth muscle cell phenotypic switching via FoxO4 suppression.
MicroRNA-23b prevents aortic aneurysm formation by inhibiting smooth muscle cell phenotypic switching via FoxO4 suppression.
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DOI：
10.1016/j.lfs.2021.119092
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发表时间：
2021-03
期刊：
影响因子：
6.1
通讯作者：
Xiaoyun Si;Qi Chen;Jiechang Zhang;Wei Zhou;Lijun Chen;Jingjing Chen;N. Deng;Wei Li;Da-nan Liu;Long Wang;Linyan Shi;Wenzhou Sun;Haoyu Song;Lintao Zhong
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文献类型：
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作者：
Xiaoyun Si;Qi Chen;Jiechang Zhang;Wei Zhou;Lijun Chen;Jingjing Chen;N. Deng;Wei Li;Da-nan Liu;Long Wang;Linyan Shi;Wenzhou Sun;Haoyu Song;Lintao Zhong
目的血管平滑肌细胞（VSMC）的表型转换对于腹主动脉瘤（AAA）的形成至关重要。microRNA-23 b（miR-23 b）最近被证明在维持VSMC收缩表型中起重要作用;然而，关于miR-23 b在AAA形成中的作用知之甚少。在这里，我们研究了miR-23 b是否通过抑制VSMC表型转换来预防AAA的形成。（Ang II，1000 ng/kg/min）或赋形剂通过皮下渗透微型泵给予10-12周龄雄性载脂蛋白E敲除（ApoE−/−）或C57 BL/6 J小鼠4周。在血管紧张素II治疗的ApoE−/−小鼠和人AAA样本中，AAA早期发作期间主动脉中的23 b显著减少。体外实验显示，miR-23 b抑制剂可加速Ang II对SMC收缩标志物基因表达的抑制作用，而模拟物可抑制Ang II对SMC收缩标志物基因表达的抑制作用。体内研究显示，与对照小鼠相比，Ang II处理的C57 BL/6 J小鼠中miR-23 b缺乏加重了这些小鼠中AAA的形成;在miR-23 b过表达小鼠中观察到相反的结果。从机制上讲，miR-23 b敲低显著增加了Ang II诱导的VSMC表型转换过程中转录因子叉头盒O 4（FoxO 4）的表达。此外，荧光素酶报告基因检测显示FoxO 4是miR-23 b在VSMCs中的靶点，我们的研究揭示了miR-23 b通过维持VSMC收缩表型在预防主动脉瘤形成中的关键作用。
AimsPhenotypic 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.Materials and methodsWe 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.Key findingsThe 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.SignificanceOur study revealed a pivotal role for miR-23b in protecting against aortic aneurysm formation by maintaining the VSMC contractile phenotype.