microRNA-22 promotes heart failure through coordinate suppression of PPAR/ERR-nuclear hormone receptor transcription

PLoS One. 2013 Sep 27;8(9):e75882. doi: 10.1371/journal.pone.0075882. eCollection 2013.


Increasing evidence suggests that microRNAs are intimately involved in the pathophysiology of heart failure. MicroRNA-22 (miR-22) is a muscle-enriched miRNA required for optimum cardiac gene transcription and adaptation to hemodynamic stress by pressure overload in mice. Recent evidence also suggests that miR-22 induces hypertrophic growth and it is oftentimes upregulated in end stage heart failure. However the scope of mRNA targets and networks of miR-22 in the heart failure remained unclear. We analyzed transgenic mice with enhanced levels of miR-22 expression in adult cardiomyocytes to identify important pathophysiologic targets of miR-22. Our data shows that forced expression of miR-22 induces a pro-hypertrophic gene expression program, and it elicits contractile dysfunction leading to cardiac dilation and heart failure. Increased expression of miR-22 impairs the Ca(2+) transient, Ca(2+) loading into the sarcoplasmic reticulum plus it interferes with transcription of estrogen related receptor (ERR) and PPAR downstream genes. Mechanistically, miR-22 postranscriptionally inhibits peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), PPARα and sirtuin 1 (SIRT1) expression via a synergistic circuit, which may account for deleterious actions of unchecked miR-22 expression on the heart.

Publication types

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

MeSH terms

  • Animals
  • Calcium / metabolism
  • Gene Expression Regulation / genetics*
  • Heart Failure / genetics*
  • Heart Failure / pathology
  • Immunoblotting
  • Luciferases
  • Mice
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Microarray Analysis
  • Peroxisome Proliferator-Activated Receptors / metabolism
  • Real-Time Polymerase Chain Reaction
  • Receptors, Estrogen / metabolism
  • Sarcoplasmic Reticulum / metabolism*
  • Sirtuin 1 / metabolism
  • Statistics, Nonparametric


  • MicroRNAs
  • Mirn22 microRNA, mouse
  • Peroxisome Proliferator-Activated Receptors
  • Receptors, Estrogen
  • Luciferases
  • Sirt1 protein, mouse
  • Sirtuin 1
  • Calcium