Functional MicroRNA Library Screening Identifies the HypoxaMiR MiR-24 as a Potent Regulator of Smooth Muscle Cell Proliferation and Vascularization
Functional MicroRNA Library Screening Identifies the HypoxaMiR MiR-24 as a Potent Regulator of Smooth Muscle Cell Proliferation and Vascularization
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DOI：
10.1089/ars.2013.5418
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发表时间：
2014-09-10
影响因子：
6.6
通讯作者：
Thum, Thomas
中科院分区：
文献类型：
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作者：
Fiedler, Jan;Stoehr, Andrea;Thum, Thomas
平滑肌细胞（SMC）是血管系统中的关键组成部分。根据刺激，SMC可以处于增殖（合成）或分化状态。SMC表型的改变也出现在几种疾病环境中，进一步促进疾病进展。目的：在这里，我们问是否microRNAs（miRNAs，miRs），这是强大的基因表达的转录后调节因子，可以改变SMC增殖。成果与创新：采用机器人辅助的高通量筛选方法，使用miRNA文库，我们确定缺氧调节的miR-24作为SMC增殖的主要调节因子。蛋白质组分析显示，miR-24对细胞应激相关因子有很强的依赖性影响，总体上导致应激抗性降低。在体外，合成的miR-24过表达对SMC功能能力有不利影响，诱导细胞凋亡、迁移缺陷、增强的自噬和收缩标记基因的丢失。SMC功能受损部分由本文鉴定的直接靶基因血红素加氧酶1介导。离体，miR-24显示出抑制工程化心脏组织模型中脉管系统的发育。结论：总的来说，我们报告的鉴定hypoxamir-24作为SMC增殖的抑制剂，有助于血管形成的损失。
Smooth muscle cells (SMCs) are key components within the vasculature. Dependent on the stimulus, SMC can either be in a proliferative (synthetic) or differentiated state. Alterations of SMC phenotype also appear in several disease settings, further contributing to disease progression. Aims: Here, we asked whether microRNAs (miRNAs, miRs), which are strong posttranscriptional regulators of gene expression, could alter SMC proliferation. Results and Innovation: Employing a robotic-assisted high-throughput screening method using miRNA libraries, we identified hypoxia-regulated miR-24 as a master regulator of SMC proliferation. Proteome profiling showed a strong miR-24-dependent impact on cellular stress-associated factors, overall resulting in reduced stress resistance. In vitro, synthetic miR-24 overexpression had detrimental effects on SMC functional capacity inducing apoptosis, migration defects, enhanced autophagy, and loss of contractile marker genes. Impaired SMC function was mediated in part by the herein identified direct target gene heme oxygenase 1. Ex vivo, miR-24 was shown to inhibit the development of vasculature in a model of engineered heart tissue. Conclusion: Collectively, we report the identification of the hypoxamir-24 as an inhibitor of SMC proliferation, contributing to loss of vascularization.