Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs
Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs
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DOI：
10.1038/ncb2441
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发表时间：
2012-03-01
影响因子：
21.3
通讯作者：
Dimmeler, Stefanie
中科院分区：
文献类型：
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作者：
Hergenreider, Eduard;Heydt, Susanne;Dimmeler, Stefanie
剪切反应性转录因子Kruppel样因子2（KLF 2）是动脉粥样硬化保护性血流诱导的内皮基因表达模式的关键调节因子。由于microRNA（miRNAs）在许多致病和生理过程中转录后调控基因表达，我们研究了KLF 2对内皮细胞miRNAs的调控。KLF 2与启动子结合并诱导miR-143/145簇的显著上调。有趣的是，miR-143/145已被证明控制平滑肌细胞（SMC）表型;因此，我们研究了这些miRNA在内皮细胞和SMC之间转运的可能性。事实上，由KLF 2转导或剪切应力刺激的HUVEC分泌的细胞外囊泡富含miR-143/145，并控制共培养的SMC中的靶基因表达。来自表达KLF 2的内皮细胞的细胞外囊泡也减少了ApoE（-/-）小鼠主动脉中动脉粥样硬化病变的形成。结合，我们的研究结果表明，动脉粥样硬化保护刺激诱导内皮细胞和SMC之间的通信通过miRNA和细胞外囊泡介导的机制，这可能包括一个有前途的战略，以打击动脉粥样硬化。
The shear-responsive transcription factor Kruppel-like factor 2 (KLF2) is a critical regulator of endothelial gene expression patterns induced by atheroprotective flow. As microRNAs (miRNAs) post-transcriptionally control gene expression in many pathogenic and physiological processes, we investigated the regulation of miRNAs by KLF2 in endothelial cells. KLF2 binds to the promoter and induces a significant upregulation of the miR-143/145 cluster. Interestingly, miR-143/145 has been shown to control smooth muscle cell (SMC) phenotypes; therefore, we investigated the possibility of transport of these miRNAs between endothelial cells and SMCs. Indeed, extracellular vesicles secreted by KLF2-transduced or shear-stress-stimulated HUVECs are enriched in miR-143/145 and control target gene expression in co-cultured SMCs. Extracellular vesicles derived from KLF2-expressing endothelial cells also reduced atherosclerotic lesion formation in the aorta of ApoE(-/-) mice. Combined, our results show that atheroprotective stimuli induce communication between endothelial cells and SMCs through an miRNA- and extracellular-vesicle-mediated mechanism and that this may comprise a promising strategy to combat atherosclerosis.