MicroRNA-23 Restricts Cardiac Valve Formation by Inhibiting Has2 and Extracellular Hyaluronic Acid Production
MicroRNA-23 Restricts Cardiac Valve Formation by Inhibiting Has2 and Extracellular Hyaluronic Acid Production
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DOI：
10.1161/circresaha.111.247635
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发表时间：
2011-09-02
影响因子：
20.1
通讯作者：
Bakkers, Jeroen
中科院分区：
文献类型：
--
作者：
Lagendijk, Anne Karine;Goumans, Marie Jose;Bakkers, Jeroen
自20年前发现以来，microRNA已被证明在组织发育和疾病过程中发挥重要作用。虽然在胚胎发育和心脏疾病的心肌microRNAs的作用已被证明，很少有人知道他们的作用，在endoorthodontal或在心脏valve formation.Objective：研究microRNAs在心脏valve formation.Methods和Results的作用：我们表明，斑马鱼dicer突变胚胎，缺乏成熟的miRNAs，形成过多的endoorthodontal垫。通过筛选心脏中表达的miRNAs，我们发现miR-23对于限制分化为内膜垫细胞的内膜细胞的数量是必要的，也是足够的。此外，在小鼠内皮细胞中，miR-23抑制了转化生长因子β诱导的内皮细胞向间充质细胞的转化。通过对预测的miR-23靶位点的表达数据进行计算机筛选并结合体内测试，我们确定了透明质酸合成酶2（Has 2）、Icat和Tmem 2为miR-23的新直接靶点。最后，我们表明，上调Has 2，细胞外重塑酶所需的内膜垫和瓣膜形成，是负责过度内膜垫细胞分化在dicer mutants.Conclusions：miR-23在胚胎心脏需要限制内膜垫形成抑制Has 2的表达和细胞外透明质酸的生产。(Circ Res. 2011;109：649-657）。
Rationale: Since their discovery almost 20 years ago, microRNAs have been shown to perform essential roles during tissue development and disease. Although roles for microRNAs in the myocardium during embryo development and cardiac disease have been demonstrated, very little is know about their role in the endocardium or during cardiac valve formation.Objective: To study the role of microRNAs in cardiac valve formation.Methods and Results: We show that zebrafish dicer mutant embryos, lacking mature miRNAs, form excessive endocardial cushions. By screening miRNAs expressed in the heart, we found that miR-23 is both necessary and sufficient for restricting the number of endocardial cells that differentiate into endocardial cushion cells. In addition, in mouse endothelial cells, miR-23 inhibited a transforming growth factor-beta-induced endothelial-to-mesenchymal transition. By in silico screening of expression data with predicted miR-23 target sites combined with in vivo testing, we identified hyaluronic acid synthase 2 (Has2), Icat, and Tmem2 as novel direct targets of miR-23. Finally, we demonstrate that the upregulation of Has2, an extracellular remodeling enzyme required for endocardial cushion and valve formation, is responsible for the excessive endocardial cushion cell differentiation in dicer mutants.Conclusions: MiR-23 in the embryonic heart is required to restrict endocardial cushion formation by inhibiting Has2 expression and extracellular hyaluronic acid production. (Circ Res. 2011;109:649-657.)