%0 Journal Article
%T microRNA-22 Promotes Heart Failure through Coordinate Suppression of PPAR/ERR-Nuclear Hormone Receptor Transcription
%A Priyatansh Gurha
%A Tiannan Wang
%A Ashley H. Larimore
%A Yassine Sassi
%A Cei Abreu-Goodger
%A Maricela O. Ramirez
%A Anilkumar K. Reddy
%A Stefan Engelhardt
%A George E. Taffet
%A Xander H. T. Wehrens
%A Mark L. Entman
%A Antony Rodriguez
%J PLOS ONE
%D 2013
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0075882
%X 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-1¦Á), PPAR¦Á and sirtuin 1 (SIRT1) expression via a synergistic circuit, which may account for deleterious actions of unchecked miR-22 expression on the heart.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0075882