Targeted Deletion of MicroRNA-22 Promotes Stress Induced Cardiac Dilation and Contractile Dysfunction
Background—Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights on how the heart adapts to pathologic stress. We developed a knockout of miR-22 in mice and investigated its function in the heart.
Methods and Results—Here we show that miR-22-deficient mice are impaired in inotropic and lusitropic response to acute stress by dobutamine. Furthermore, absence of miR-22 sensitized mice to cardiac decompensation and LV dilation following chronic stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum (SR) Ca2+ load in association with repressed SR Ca+2 ATPase (SERCA2a) activity in mutant myocytes. Genetic ablation of miR-22 also led to a decrease in cardiac expression levels for Serca2a and muscle-restricted genes encoding proteins in the vicinity of the cardiac Z disc/Titin cytoskeleton. These phenotypes were attributed, in part, to inappropriate repression of Serum response factor (SRF) activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B (PURB) a highly conserved miR-22 target implicated in negative control of muscle expression.
Conclusions—This data indicates miR-22 functions as an integrator of Ca+2 homeostasis and myofibrillar protein content during stress in the heart and it sheds light on the mechanisms that enhance propensity toward heart failure (HF).
- Received May 17, 2011.
- Accepted April 10, 2012.
- Copyright © 2012, American Heart Association, Inc. All rights reserved. Unauthorized use prohibited