title: 17β-Estradiol-induced interaction of estrogen receptor α and human atrial essential myosin light chain modulates cardiac contractile function.
abstract: Chronic increased workload of the human heart causes ventricular hypertrophy, re-expression of the atrial essential myosin light chain (hALC-1), and improved contractile function. Although hALC-1 is an important positive inotropic regulator of the human heart, little is known about its regulation. Therefore, we investigated the role of the sex hormone 17β-estradiol (E2) on hALC-1 gene expression, the underlying molecular mechanisms, and the impact of this regulatory process on cardiac contractile function. We showed that E2 attenuated hALC-1 expression in human atrial tissues of both sexes and in human ventricular AC16 cells. E2 induced the nuclear translocation of estrogen receptor alpha (ERα) and hALC-1 in AC16 cells, where they cooperatively regulate the transcriptional activity of hALC-1 gene promoter. E2-activated ERα required the estrogen response element (ERE) motif within the hALC-1 gene promoter to reduce its transcriptional activity (vehicle: 15.55 ± 4.80 vs. E2: 6.51 ± 3.69; ~2 fold). This inhibitory effect was potentiated in the presence of hALC-1 (vehicle: 11.13 ± 3.66 vs. E2: 2.18 ± 1.10; ~5 fold), and thus, hALC-1 acts as a co-repressor of ERα-mediated transcription. Yeast two-hybrid screening of a human heart cDNA library revealed that ERα interacts physically with hALC-1 in the presence of E2. This interaction was confirmed by Co-Immunoprecipitation and immunofluorescence in human atrium. As a further novel effect, we showed that chronic E2-treatment of adult mouse cardiomyocytes overexpressing hALC-1 resulted in reduced cell-shortening amplitude and twitching kinetics of these cells independent of Ca2+activation levels. Together, our data showed that the expression of hALC-1 gene is, at least partly, regulated by E2/ERα, while hALC-1 acts as a co-repressor. The inotropic effect of hALC-1 overexpression in cardiomyocytes can be significantly repressed by E2.
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Roessle-Str. 10, 13125, Berlin, Germany.
authors.forename: Karolin
authors.initials: K
authors.lastname: Duft
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charité Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Miriam
authors.initials: M
authors.lastname: Schanz
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charité Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Hang
authors.initials: H
authors.lastname: Pham
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Roessle-Str. 10, 13125, Berlin, Germany.
authors.forename: Ahmed
authors.initials: A
authors.lastname: Abdelwahab
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Roessle-Str. 10, 13125, Berlin, Germany.
authors.forename: Cindy
authors.initials: C
authors.lastname: Schriever
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charité Universitaetsmedizin Berlin, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charité Universitaetsmedizin Berlin, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Dworatzek
authors.affiliation: Department of Radiation Oncology, Columbia University, New York, USA.
authors.forename: Mercy M
authors.initials: MM
authors.lastname: Davidson
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research, Charité Universitaetsmedizin Berlin, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Roessle-Str. 10, 13125, Berlin, Germany.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany.
authors.forename: Ingo
authors.initials: I
authors.lastname: Morano
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Robert-Roessle-Str. 10, 13125, Berlin, Germany. shokoufeh.mahmoodzadeh@mdc-berlin.de.|DZHK (German Center for Cardiovascular Research), partner site Berlin, Berlin, Germany. shokoufeh.mahmoodzadeh@mdc-berlin.de.
authors.forename: Shokoufeh
authors.initials: S
authors.lastname: Mahmoodzadeh
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004958:Estradiol / Q000378:metabolism*; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D005786:Gene Expression Regulation / Q000235:genetics*; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D009200:Myocardial Contraction / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018994:Myosin Light Chains / Q000096:biosynthesis* / Q000235:genetics; D016133:Polymerase Chain Reaction; D020798:Two-Hybrid System Techniques
chemical_list: D047628:Estrogen Receptor alpha; D018994:Myosin Light Chains; C491915:hALC-1 protein, human; D004958:Estradiol
keywords: 17β-estradiol; Atrial essential myosin light chain; Cardiac contractile function; Estrogen receptor alpha; Transcriptional/translational regulation