Conditional Dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling
Conditional Dicer gene deletion in the postnatal myocardium provokes spontaneous cardiac remodeling
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DOI：
10.1161/circulationaha.108.769984
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发表时间：
2008-10-07
期刊：
影响因子：
37.8
通讯作者：
De Windt, Leon J.
中科院分区：
文献类型：
--
作者：
Martins, Paula A. da Costa;Bourajjaj, Meriem;De Windt, Leon J.
背景-Dicer是一种RNAse III内切核酸酶，其对于将前体microRNA（miRNAs）加工成成熟的22-核苷酸miRNAs至关重要，已被证明是剖析miRNAs生物发生在哺乳动物生物学中的重要性的有用靶标。我们通过在出生后的小鼠心肌中使用他莫昔芬诱导的Cre重组酶来触发条件性Dicer丧失。在3周龄小鼠中靶向Dicer缺失在1周内引起过早死亡，伴随轻度心室重构和显著心房增大。在成年心肌中，Dicer的缺失诱导快速和显著的双心室扩大，伴随着肌细胞肥大、肌纤维紊乱、心室纤维化和胎儿基因转录的强烈诱导。比较miRNA分析揭示了一组miRNA，这意味着miRNA消耗和自发性心脏remodels.Conclusions-Overall之间的因果关系，这些结果表明，在miRNA生物发生的修改影响青少年和成人心肌的形态和功能。
Background-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.Methods and Results-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.Conclusions-Overall, these results indicate that modifications in miRNA biogenesis affect both juvenile and adult myocardial morphology and function.