da Costa Martins Paula A, Bourajjaj Meriem, Gladka Monika, Kortland Mara, van Oort Ralph J, Pinto Yigal M, Molkentin Jeffery D, De Windt Leon J
Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands.
Circulation. 2008 Oct 7;118(15):1567-76. doi: 10.1161/CIRCULATIONAHA.108.769984. Epub 2008 Sep 22.
Dicer, an RNAse III endonuclease critical for processing of pre-microRNAs (miRNAs) into mature 22-nucleotide miRNAs, has proven a useful target to dissect the significance of miRNAs biogenesis in mammalian biology.
To circumvent the embryonic lethality associated with germline null mutations for Dicer, we triggered conditional Dicer loss through the use of a tamoxifen-inducible Cre recombinase in the postnatal murine myocardium. Targeted Dicer deletion in 3-week-old mice provoked premature death within 1 week accompanied by mild ventricular remodeling and dramatic atrial enlargement. In the adult myocardium, loss of Dicer induced rapid and dramatic biventricular enlargement, accompanied by myocyte hypertrophy, myofiber disarray, ventricular fibrosis, and strong induction of fetal gene transcripts. Comparative miRNA profiling revealed a set of miRNAs that imply causality between miRNA depletion and spontaneous cardiac remodeling.
Overall, these results indicate that modifications in miRNA biogenesis affect both juvenile and adult myocardial morphology and function.
Dicer是一种RNA酶III内切核酸酶，对将前体微小RNA（miRNA）加工成成熟的22个核苷酸的miRNA至关重要，它已被证明是剖析miRNA生物合成在哺乳动物生物学中的意义的有用靶点。
为了规避与Dicer种系无效突变相关的胚胎致死性，我们通过在出生后小鼠心肌中使用他莫昔芬诱导的Cre重组酶来引发条件性Dicer缺失。在3周龄小鼠中靶向删除Dicer会在1周内引发过早死亡，伴有轻度心室重塑和显著的心房扩大。在成年心肌中，Dicer缺失会导致快速且显著的双心室扩大，伴有心肌细胞肥大、肌纤维紊乱、心室纤维化以及胎儿基因转录本的强烈诱导。比较性miRNA谱分析揭示了一组miRNA，提示miRNA缺失与自发性心脏重塑之间存在因果关系。
总体而言，这些结果表明miRNA生物合成的改变会影响幼年和成年心肌的形态与功能。
