Abstract
Background-Delineating the role of microRNAs (miRNAs) in the posttranscriptional gene regulation offers new insights into how the heart adapts to pathological 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, the absence of miR-22 sensitized mice to cardiac decompensation and left ventricular dilation after long-term stimulation by pressure overload. Calcium transient analysis revealed reduced sarcoplasmic reticulum Ca load in association with repressed sarcoplasmic reticulum Ca ATPase 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 disk/titin cytoskeleton. These phenotypes were attributed in part to inappropriate repression of serum response factor activity in stressed hearts. Global analysis revealed increased expression of the transcriptional/translational repressor purine-rich element binding protein B, a highly conserved miR-22 target implicated in the negative control of muscle expression. CONCLUSION-: These data indicate that miR-22 functions as an integrator of Ca homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.
Original language | English (US) |
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Pages (from-to) | 2751-2761 |
Number of pages | 11 |
Journal | Circulation |
Volume | 125 |
Issue number | 22 |
DOIs | |
State | Published - Jun 5 2012 |
Keywords
- Cardiomyopathy, dilated
- Heart failure
- MicroRNAs
- Myocardial contraction
- Sarcomeres
ASJC Scopus subject areas
- Physiology (medical)
- Cardiology and Cardiovascular Medicine