MicroRNA-15b/16 Attenuates Vascular Neointima Formation by Promoting the Contractile Phenotype of Vascular Smooth Muscle Through Targeting YAP.
MicroRNA-15b/16 Attenuates Vascular Neointima Formation by Promoting the Contractile Phenotype of Vascular Smooth Muscle Through Targeting YAP.
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DOI：
10.1161/atvbaha.115.305748
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发表时间：
2015-10
期刊：
影响因子：
--
通讯作者：
Zhou J
中科院分区：
文献类型：
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作者：
Xu F;Ahmed AS;Kang X;Hu G;Liu F;Zhang W;Zhou J
探讨miR-15b/16在血管平滑肌表型调节中的功能作用。我们发现miR-15b/16是收缩性血管平滑肌细胞（VSMCs）中表达最丰富的microrna之一。然而，当收缩的vsmc转化为合成表型时，miR-15b/16的表达显著降低。在VSMC中敲低内源性miR-15b/16会减弱平滑肌特异性基因的表达，但会促进VSMC的增殖和迁移。相反，过表达miR-15b/16促进平滑肌收缩基因的表达，同时减弱VSMC的迁移和增殖。与此一致的是，在大鼠颈动脉球囊损伤模型中，过表达miR-15b/16可显著减弱损伤诱导的平滑肌去分化和新内膜形成。在机制上，我们确定了强效癌蛋白yes-associated protein （YAP）是VSMCs中miR-15b/16的下游靶点。报告者试验证实miR-15b/16靶向YAP的3 ' -未翻译区。此外，过表达miR-15b/16会显著抑制YAP表达，反之，内源性miR-15b/16的缺失会导致YAP表达上调。这些结果表明，miR-15b/16至少部分通过靶向YAP在平滑肌表型调节中起关键作用。恢复miR-15b/16的表达将是治疗增殖性血管疾病的潜在治疗方法。
To investigate the functional role of the miR-15b/16 in vascular smooth muscle phenotypic modulation. We found that miR-15b/16 is the one of most abundant microRNAs expressed in contractile vascular smooth muscle cells (VSMCs). However, when contractile VSMCs convert to a synthetic phenotype miR-15b/16 expression is significantly reduced. Knocking-down endogenous miR-15b/16 in VSMCs attenuates smooth muscle-specific gene expression but promotes VSMC proliferation and migration. Conversely, over-expression of miR-15b/16 promotes smooth muscle contractile gene expression while attenuating VSMC migration and proliferation. Consistent with this, over-expression of miR-15b/16 in a rat carotid balloon injury model markedly attenuates injury-induced smooth muscle de-differentiation and neointima formation. Mechanistically, we identified the potent oncoprotein yes-associated protein (YAP) as a downstream target of miR-15b/16 in VSMCs. Reporter assays validated that miR-15b/16 targets YAP’s 3′-untranslated region. Moreover, overexpression of miR-15b/16 significantly represses YAP expression, whereas conversely, depletion of endogenous miR-15b/16 results in up-regulation of YAP expression. These results indicate that miR-15b/16 plays a critical role in smooth muscle phenotypic modulation at least partly through targeting YAP. Restoring expression of miR-15b/16 would be a potential therapeutic approach for treatment of proliferative vascular diseases.