Targeted Deletion of MicroRNA-22 Promotes Stress-Induced Cardiac Dilation and Contractile Dysfunction
- 5 June 2012
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 125 (22), 2751-2761
- https://doi.org/10.1161/circulationaha.111.044354
Abstract
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. 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 2+ load in association with repressed sarcoplasmic reticulum Ca 2+ 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. These data indicate that miR-22 functions as an integrator of Ca 2+ homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.Keywords
This publication has 39 references indexed in Scilit:
- Attenuation of MicroRNA‐22 derepressed PTEN to effectively protect rat cardiomyocytes from hypertrophyJournal of Cellular Physiology, 2011
- Serum response factor micromanaging cardiogenesisCurrent Opinion in Cell Biology, 2007
- Sarcomeric proteins and inherited cardiomyopathiesCardiovascular Research, 2007
- Factors controlling cardiac myosin-isoform shift during hypertrophy and heart failureJournal of Molecular and Cellular Cardiology, 2007
- Ca2+- and mitochondrial-dependent cardiomyocyte necrosis as a primary mediator of heart failureJCI Insight, 2007
- Control of Stress-Dependent Cardiac Growth and Gene Expression by a MicroRNAScience, 2007
- The single-strand DNA/RNA-binding protein, Purβ, regulates serum response factor (SRF)-mediated cardiac muscle gene expressionThis paper is one of a selection of papers published in this Special Issue, entitled The Cellular and Molecular Basis of Cardiovascular Dysfunction, Dhalla 70th Birthday Tribute.Canadian Journal of Physiology and Pharmacology, 2007
- Purα and Purβ Collaborate with Sp3 To Negatively Regulate β-Myosin Heavy Chain Gene Expression duringSkeletal Muscle InactivityMolecular and Cellular Biology, 2007
- Decompensation of Cardiac Hypertrophy: Cellular Mechanisms and Novel Therapeutic TargetsPhysiology, 2007
- TP53INP1 is a novel p73 target gene that induces cell cycle arrest and cell death by modulating p73 transcriptional activityOncogene, 2005