title: Direct and indirect involvement of microRNA-499 in clinical and experimental cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  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.
authors: Department of Internal Medicine, Center for Pharmacogenomics, 660 S Euclid Ave, Campus Box 8220, St Louis, MO 63110, USA. smatkovi@dom.wustl.edu
authors: Scot J
authors: SJ
authors: Matkovich
authors: Yuanxin
authors: Y
authors: Hu
authors: William H
authors: WH
authors: Eschenbacher
authors: Lisa E
authors: LE
authors: Dorn
authors: Gerald W
authors: GW
authors: Dorn
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000502:physiology; D020869:Gene Expression Profiling; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics* / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000502:physiology; D040901:Proteomics; D019076:Transgenes / Q000502:physiology
chemical_list: D018841:HSP90 Heat-Shock Proteins; C548683:MIRN499 microRNA, human; D035683:MicroRNAs; D054645:Protein Phosphatase 1