Targeted deletion of microRNA-22 promotes stress-induced cardiac dilation and contractile dysfunction

Circulation. 2012 Jun 5;125(22):2751-61. doi: 10.1161/CIRCULATIONAHA.111.044354. Epub 2012 May 8.


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(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.

Conclusion: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cardiomyopathy, Dilated / metabolism*
  • Cardiomyopathy, Dilated / pathology
  • Cardiomyopathy, Dilated / physiopathology*
  • DNA-Binding Proteins / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / physiology
  • Homeostasis / physiology
  • Male
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism*
  • Myocardial Contraction / physiology*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / metabolism
  • Serum Response Factor / metabolism
  • Stress, Physiological / physiology*


  • DNA-Binding Proteins
  • MicroRNAs
  • Mirn22 microRNA, mouse
  • Purb protein, mouse
  • Serum Response Factor
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Calcium