Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure
Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure
复制标题
DOI：
10.1073/pnas.0710228105
复制
发表时间：
2008-02-12
影响因子：
11.1
通讯作者：
Wang, Da-Zhi
中科院分区：
文献类型：
--
作者：
Chen, Jian-Fu;Murchison, Elizabeth P.;Wang, Da-Zhi
心血管疾病是人类发病率和死亡率的主要原因。扩张型心肌病（DCM）是与心力衰竭相关的最常见的心肌病形式。在这里，我们报告了心脏特异性敲除Dicer（一种编码微小RNA（miRNA）加工所必需的RNase III内切核酸酶的基因）导致快速进展的DCM、心力衰竭和出生后致死。Dicer突变小鼠表现出心肌收缩蛋白的错误表达和严重的肌节混乱。功能分析表明Dicer突变心脏的心率显著降低，缩短率降低。与Dicer在动物心脏中的作用一致，Dicer表达在终末期人DCM和衰竭心脏中降低，并且最重要的是，在插入左心室辅助装置以改善心脏功能后，在这些心脏中观察到Dicer表达的显著增加。总之，我们的研究证明了Dicer在心脏收缩中的重要作用，并表明miRNA在正常心脏功能和病理条件下发挥关键作用。
Cardiovascular disease is the leading cause of human morbidity and mortality. Dilated cardiomyopathy (DCM) is the most common form of cardiomyopathy associated with heart failure. Here, we report that cardiac-specific knockout of Dicer, a gene encoding a RNase III endonuclease essential for microRNA (miRNA) processing, leads to rapidly progressive DCM, heart failure, and postnatal lethality. Dicer mutant mice show misexpression of cardiac contractile proteins and profound sarcomere disarray. Functional analyses indicate significantly reduced heart rates and decreased fractional shortening of Dicer mutant hearts. Consistent with the role of Dicer in animal hearts, Dicer expression was decreased in end-stage human DCM and failing hearts and, most importantly, a significant increase of Dicer expression was observed in those hearts after left ventricle assist devices were inserted to improve cardiac function. Together, our studies demonstrate essential roles for Dicer in cardiac contraction and indicate that miRNAs play critical roles in normal cardiac function and under pathological conditions.