title: Elevated miR-499 levels blunt the cardiac stress response.
abstract: BACKGROUND
  The heart responds to myriad stresses by well-described transcriptional responses that involve long-term changes in gene expression as well as more immediate, transient adaptations. MicroRNAs quantitatively regulate mRNAs and thus may affect the cardiac transcriptional output and cardiac function. Here we investigate miR-499, a microRNA embedded within a ventricular-specific myosin heavy chain gene, which is expressed in heart and skeletal muscle.
  
  
  RESULTS
  We assessed miR-499 expression in human tissue to confirm its potential relevance to human cardiac gene regulation. Using a transgenic mouse model, we found that elevated miR-499 levels caused cellular hypertrophy and cardiac dysfunction in a dose-dependent manner. Global gene expression profiling revealed altered levels of the immediate early stress response genes (Egr1, Egr2 and Fos), ß-myosin heavy chain (Myh7), and skeletal muscle actin (Acta1). We verified the effect of miR-499 on the immediate early response genes by miR-499 gain- and loss-of-function in vitro. Consistent with a role for miR-499 in blunting the response to cardiac stress, asymptomatic miR-499-expressing mice had an impaired response to pressure overload and accentuated cardiac dysfunction.
  
  
  CONCLUSIONS
  Elevated miR-499 levels affect cardiac gene expression and predispose to cardiac stress-induced dysfunction. miR-499 may titrate the cardiac response to stress in part by regulating the immediate early gene response.
authors.affiliation: Gladstone Institute of Cardiovascular Disease, San Francisco, California, United States of America.
authors.forename: Joseph T C
authors.initials: JT
authors.lastname: Shieh
authors.forename: Yu
authors.initials: Y
authors.lastname: Huang
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Gilmore
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000199:Actins / Q000235:genetics; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D051766:Early Growth Response Protein 1 / Q000235:genetics; D051767:Early Growth Response Protein 2 / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D018995:Myosin Heavy Chains / Q000235:genetics; D016133:Polymerase Chain Reaction; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D055755:SOXD Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000199:Actins; D051766:Early Growth Response Protein 1; D051767:Early Growth Response Protein 2; C486109:Egr1 protein, mouse; C497327:Egr2 protein, mouse; C548683:MIRN499 microRNA, human; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; C486270:SOX6 protein, human; D055755:SOXD Transcription Factors; D018995:Myosin Heavy Chains