title: Cohort of estrogen-induced microRNAs regulate adrenomedullin expression.
abstract: Estrogen regulates the expression of many genes and has been correlated with differences in cardiac contraction; however, the underlying mechanisms remain poorly defined. Adrenomedullin (Adm = gene; AM = protein) is a multifunctional peptide with inotropic actions. Previous studies have demonstrated that estrogen enhances the expression of Adm, suggesting a relationship between AM and estrogen in cardiac contraction during physiological and pathological states. In this study, female mice in a mouse model of genetic Adm overexpression, abbreviated as Adm(hi/hi), were found to express 60 times more Adm in the heart than wild-type littermates, compared with the three-fold elevation of Adm previously reported in Adm(hi/hi) male hearts. Thus, this study sought to further investigate any functional consequences of increased cardiac Adm expression and begin exploring the mechanisms that regulate Adm expression in an estrogen-dependent fashion. This study revealed that heart function is enhanced in Adm(hi/hi) females, which along with Adm expression levels, was reversed following ovariectomization. Since the Adm(hi/hi) line was generated by the displacement of the 3' untranslated region (UTR), the native 3'UTR was examined for estrogen-induced microRNAs target sites to potentially explain the aberrant overexpression observed in Adm(hi/hi) female hearts. Using a bioinformatic approach, it was determined that the mouse Adm 3'UTR contains many target sites for previously characterized estrogen-induced microRNAs. This study also determined that the novel microRNA, miR-879, is another estrogen-induced microRNA that interacts with the 3'UTR of Adm to destabilize the mRNA. Together, these studies revealed that estrogen-induced microRNAs are important for balancing cardiac Adm expression in females.
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, North Carolina; and.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wetzel-Strong
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, North Carolina; and.
authors.forename: Manyu
authors.initials: M
authors.lastname: Li
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, North Carolina; and.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Espenschied
authors.affiliation: Departments of Cell Biology and Physiology, University of North Carolina at Chapel Hill, North Carolina; and Department of Genetics, University of North Carolina at Chapel Hill, North Carolina kathleen_caron@med.unc.edu.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Caron
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D053607:Adrenomedullin / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites; D019295:Computational Biology; D030541:Databases, Genetic; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D013006:Growth Hormone / Q000235:genetics; D006439:Hemodynamics; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D010052:Ovariectomy; D010641:Phenotype; D015398:Signal Transduction; D015854:Up-Regulation; D016277:Ventricular Function, Left
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D004967:Estrogens; D035683:MicroRNAs; D053607:Adrenomedullin; D013006:Growth Hormone
keywords: adrenomedullin; contractility; estrogen; microRNAs