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 (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.
Chen
Jian-Fu
JF
Carolina Cardiovascular Biology Center, Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599, USA.
Murchison
Elizabeth P
EP
Tang
Ruhang
R
Callis
Thomas E
TE
Tatsuguchi
Mariko
M
Deng
Zhongliang
Z
Rojas
Mauricio
M
Hammond
Scott M
SM
Schneider
Michael D
MD
Selzman
Craig H
CH
Meissner
Gerhard
G
Patterson
Cam
C
Hannon
Gregory J
GJ
Wang
Da-Zhi
DZ
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002311:Cardiomyopathy, Dilated / Q000201:enzymology* / Q000235:genetics; D006333:Heart Failure / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics; D009154:Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics / Q000502:physiology*
D035683:MicroRNAs; D043244:Ribonuclease III