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

Priyatansh Gurha, Cei Abreu-Goodger, Tiannan Wang, Maricela O. Ramirez, Ana L. Drumond, Stijn Van Dongen, Yuqing Chen, Nenad Bartonicek, Anton J. Enright, Brendan Lee, Robert J. Kelm, Anilkumar K. Reddy, George Taffet, Allan Bradley, Xander H. Wehrens, Mark L. Entman, Antony Rodriguez

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

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 load in association with repressed sarcoplasmic reticulum Ca 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 homeostasis and myofibrillar protein content during stress in the heart and shed light on the mechanisms that enhance propensity toward heart failure.

Original languageEnglish (US)
Pages (from-to)2751-2761
Number of pages11
JournalCirculation
Volume125
Issue number22
DOIs
StatePublished - Jun 5 2012

Keywords

  • Cardiomyopathy, dilated
  • Heart failure
  • MicroRNAs
  • Myocardial contraction
  • Sarcomeres

ASJC Scopus subject areas

  • Physiology (medical)
  • Cardiology and Cardiovascular Medicine

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