Molecular Cardiology 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 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 2ϩ load in association with repressed sarcoplasmic reticulum Ca 2ϩ 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 2ϩ homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure. C ardiac hypertrophy may initially develop as an adaptive response aimed at increasing heart function and normalizing wall stress to hemodynamic (pressure or volume) overload generated by pathological stresses such as hyperten-sion or other myocardial injuries. Although compensatory cardiac hypertrophy seems beneficial at first, prolonged cardiac hypertrophy is correlated with poor clinical prognosis, eventually leading to maladaptive organ-level changes such as thinning of ventricular walls, dilatation, and diminished cardiac contrac-tility, eventually leading to heart failure. 1 Pathological cardiac hypertrophy is characterized by tran-scriptional reactivation of a fetal gene program, induction of hypertrophic genes, and adaptive and maladaptive changes in expression levels of sarcoplasmic reticulum Ca 2ϩ ATPase activity (SERCA2) and other important contractile proteins. 1– 4 At the molecular level, reduced expression or activity of SERCA2a is one of the hallmarks of heart failure. 3 SERCA2a is a critical determinant of cardiac contractility responsible for Ca 2ϩ reuptake from cytosol during excitation-contraction coupling. 5,6 SERCA2a expression and fetal/cardiac hypertrophy genes are under direct transcription control by the serum response factor (SRF), a MADS box transcription factor. 7,8 SRF controls gene expression by binding to discrete DNA sequences known as CArG elements [CC(A/T) …