title: Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart.
abstract: BACKGROUND
  In pressure overload, profibrotic gene expression and cardiac fibrosis are more pronounced in males than in females. Sex-specific and estrogen-dependent regulation of microRNAs (miRNAs), such as miR-21, may be a potential mechanism leading to sex differences in fibrosis.
  
  
  OBJECTIVE
  To analyze the influence of sex, estrogen, and estrogen receptor beta (ERβ) on the expression of miR-21 and to identify additional miRNAs potentially involved in sex-specific pressure overload-induced cardiac remodeling.
  
  
  METHODS
  The sex-specific regulation of fibrosis-related miRNAs was analyzed in male and female wild type and ERβ-deficient mice after transverse aortic constriction (TAC), in rat fibroblasts, and in a cardiomyocyte-like cell line.
  
  
  RESULTS
  We report the sex-specific expression of functionally-related miR-21, -24, -27a, -27b, 106a, -106b and the regulation of their expression by estrogen in a sex-specific manner. These effects were abolished in ERβ-deficient mice. We demonstrate the presence of common functional target sites for these miRNAs on three repressors of the mitogen-activated protein kinase signaling pathway, i.e. Rasa1, Rasa2 and Spry1, which may all lead to cardiac fibrosis. As expected, transfection with miRNA mimics targeting these repressors induced ERK1/2 phosphorylation.
  
  
  CONCLUSIONS
  Estrogen regulates a network of miRNAs in a sex-specific manner via ERβ. Our data suggest that the sex-specific expression of these miRNAs may be related to sex differences in fibrosis after pressure overload.
authors.affiliation: Institute of Gender in Medicine (GiM)/Center for Cardiovascular Research (CCR), Charité-Universitätsmedizin Berlin, Berlin, Germany. Electronic address: ana-maria.queiros@charite.de.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Queirós
authors.forename: Claudia
authors.initials: C
authors.lastname: Eschen
authors.forename: Daniela
authors.initials: D
authors.lastname: Fliegner
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.forename: Elke
authors.initials: E
authors.lastname: Dworatzek
authors.forename: Christina
authors.initials: C
authors.lastname: Westphal
authors.forename: Hugo
authors.initials: H
authors.lastname: Sanchez Ruderisch
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000818:Animals; D002460:Cell Line; D002478:Cells, Cultured; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000502:physiology*; D004967:Estrogens / Q000502:physiology; D005260:Female; D005355:Fibrosis; D053263:Gene Regulatory Networks / Q000502:physiology; D006321:Heart / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000473:pathology* / Q000502:physiology*; D051381:Rats; D012727:Sex Characteristics
chemical_list: D047629:Estrogen Receptor beta; D004967:Estrogens; D035683:MicroRNAs
keywords: Estradiol; Estrogen receptor beta; Hypertrophy; Sex-specific; miRNAs