Targeted deletion of Dicer in the heart leads to dilated cardiomyopathy and heart failure

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...

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Published in:Proceedings of the National Academy of Sciences - PNAS 2008-02, Vol.105 (6), p.2111-2116
Main Authors: Chen, Jian-Fu, Murchison, Elizabeth P, Tang, Ruhang, Callis, Thomas E, Tatsuguchi, Mariko, Deng, Zhongliang, Rojas, Mauricio, Hammond, Scott M, Schneider, Michael D, Selzman, Craig H, Meissner, Gerhard, Patterson, Cam, Hannon, Gregory J, Wang, Da-Zhi
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Blotting, Northern
Blotting, Western
Cardiac output
Cardiomyopathy, Dilated - enzymology
Cardiomyopathy, Dilated - genetics
Contractile proteins
Developmental biology
Dilated cardiomyopathy
Gene expression
Heart
Heart assist devices
Heart failure
Heart Failure - enzymology
Heart Failure - genetics
Humans
Immunohistochemistry
In Situ Nick-End Labeling
Mice
Mice, Knockout
MicroRNA
MicroRNAs - genetics
Mutation
Myocardium
Reverse Transcriptase Polymerase Chain Reaction
Ribonuclease III - genetics
Ribonuclease III - physiology
Ribonucleic acid
RNA
Rodents
Sarcomeres
Studies
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0710228105