Sex- and estrogen-dependent regulation of a miRNA network in the healthy and hypertrophied heart


  • A.M. Queiros
  • C. Eschen
  • D. Fliegner
  • G. Kararigas
  • E. Dworatzek
  • C. Westphal
  • H. Sanchez Ruderisch
  • V. Regitz-Zagrosek


  • International Journal of Cardiology


  • Int J Cardiol 169 (5): 331-338


  • 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. OBJECTIVES: To analyze the influence of sex, estrogen, and estrogen receptor {beta} (ER{beta}) 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 ER{beta}-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 ER{beta}-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 ER{beta}. Our data suggest that the sex-specific expression of these miRNAs may be related to sex differences in fibrosis after pressure overload.