Direct and indirect involvement of microRNA-499 in clinical and experimental cardiomyopathy

Circ Res. 2012 Aug 17;111(5):521-31. doi: 10.1161/CIRCRESAHA.112.265736. Epub 2012 Jun 29.


Rationale: MicroRNA-499 and other members of the myomiR family regulate myosin isoforms in pressure-overload hypertrophy. miR-499 expression varies in human disease, but results of mouse cardiac miR-499 overexpression are inconsistent, either protecting against ischemic damage or aggravating cardiomyopathy after pressure overload. Likewise, there is disagreement over direct and indirect cardiac mRNAs targeted in vivo by miR-499.

Objective: To define the associations between regulated miR-499 level in clinical and experimental heart disease and modulation of its predicted mRNA targets and to determine the consequences of increased cardiac miR-499 on direct mRNA targeting, indirect mRNA modulation, and on myocardial protein content and posttranslational modification.

Methods and results: miR-499 levels were increased in failing and hypertrophied human hearts and associated with decreased levels of predicted target mRNAs. Likewise, miR-499 is increased in Gq-mediated murine cardiomyopathy. Forced cardiomyocyte expression of miR-499 at levels comparable to human cardiomyopathy induced progressive murine heart failure and exacerbated cardiac remodeling after pressure overloading. Genome-wide RNA-induced silencing complex and RNA sequencing identified 67 direct, and numerous indirect, cardiac mRNA targets, including Akt and MAPKs. Myocardial proteomics identified alterations in protein phosphorylation linked to the miR-499 cardiomyopathy phenotype, including of heat shock protein 90 and protein serine/threonine phosphatase 1-α.

Conclusions: miR-499 is increased in human and murine cardiac hypertrophy and cardiomyopathy, is sufficient to cause murine heart failure, and accelerates maladaptation to pressure overloading. The deleterious effects of miR-499 reflect the cumulative consequences of direct and indirect mRNA regulation, modulation of cardiac kinase and phosphatase pathways, and higher-order effects on posttranslational modification of myocardial proteins.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aging / physiology
  • Animals
  • Cardiomegaly / genetics
  • Cardiomegaly / metabolism
  • Cardiomegaly / physiopathology
  • Cardiomyopathies* / genetics
  • Cardiomyopathies* / metabolism
  • Cardiomyopathies* / physiopathology
  • Disease Models, Animal
  • Down-Regulation / physiology
  • Gene Expression Profiling
  • HSP90 Heat-Shock Proteins / metabolism
  • Heart Failure* / genetics
  • Heart Failure* / metabolism
  • Heart Failure* / physiopathology
  • Humans
  • MAP Kinase Signaling System / genetics*
  • MAP Kinase Signaling System / physiology
  • Mice
  • Mice, Transgenic
  • MicroRNAs / physiology*
  • Phosphorylation / physiology
  • Protein Phosphatase 1 / metabolism
  • Protein Processing, Post-Translational / physiology
  • Proteomics
  • Transgenes / physiology


  • HSP90 Heat-Shock Proteins
  • MIRN499 microRNA, human
  • MicroRNAs
  • Protein Phosphatase 1