microRNA-22 Promotes Heart Failure through Coordinate Suppression of PPAR/ERR-Nuclear Hormone Receptor Transcription

Priyatansh Gurha, Tiannan Wang, Ashley H. Larimore, Yassine Sassi, Cei Abreu-Goodger, Maricela O. Ramirez, Anilkumar K. Reddy, Stefan Engelhardt, George Taffet, Xander H.T. Wehrens, Mark L. Entman, Antony Rodriguez

Research output: Contribution to journalArticle

58 Scopus citations

Abstract

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 Ca2+ transient, Ca2+ 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.

Original languageEnglish (US)
Article numbere75882
JournalPLoS ONE
Volume8
Issue number9
DOIs
StatePublished - Sep 27 2013

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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