title: Genetic background defines the regulation of postnatal cardiac growth by 17β-estradiol through a β-catenin mechanism.
abstract: Estrogen regulates several biological processes in health and disease. Specifically, estrogen exerts antihypertrophic effects in the diseased heart. However, its role in the healthy heart remains elusive. Our initial aim was to identify the effects of 17β-estradiol (E2) on cardiac morphology and global gene expression in the healthy mouse heart. Two-month-old C57BL/6J mice were ovariectomized and treated with E2 or vehicle for 3 months. We report that E2 induced physiological hypertrophic growth in the healthy C57BL/6J mouse heart characterized by an increase in nuclear β-catenin. Hypothesizing that β-catenin mediates these effects of E2, we employed a model of cardiac β-catenin deletion. Our surprising finding is that E2 had the opposite effects in wild-type littermates, which were actually on the C57BL/6N background. Notably, E2 exerted no significant effect in hearts of mice with depleted β-catenin. We further demonstrate an E2-dependent increase in glycogen synthase kinase 3β (GSK3β) phosphorylation and endosomal markers in C57BL/6J but not C57BL/6N mice. Together, these findings indicate an E2-driven inhibition of GSK3β and consequent activation of β-catenin in C57BL/6J mice, whereas the opposite occurs in C57BL/6N mice. In conclusion, E2 exerts divergent effects on postnatal cardiac growth in mice with distinct genetic backgrounds modulating members of the GSK3β/β-catenin cascade.
authors.affiliation: Institute of Gender in Medicine and Center for Cardiovascular Research (G.K., H.S.-R., V.R.-Z.), Charite University Hospital, and DZHK (German Center for Cardiovascular Research), Berlin Partner Site, 10115 Berlin, Germany; Department of Clinical and Experimental Endocrinology (B.T.N., M.H., H.J.), Goettingen University, 37075 Goettingen, Germany; Department of Pharmacology (L.C.Z.), Heart Research Center Goettingen, and Department of Cardiology and Pneumology (K.T., G.H.), Georg-August-University Goettingen, and DZHK (German Center for Cardiovascular Research), Goettingen Partner Site, 37075 Goettingen, Germany; and Department of Cardiology (M.W.B.), Asklepios Klinik St Georg, 20099 Hamburg, Germany; and Faculty of Veterinary Medicine (B.T.N.), Hanoi University of Agriculture, Hanoi, Vietnam.
authors.forename: Georgios
authors.initials: G
authors.lastname: Kararigas
authors.forename: Ba Tiep
authors.initials: BT
authors.lastname: Nguyen
authors.forename: Laura C
authors.initials: LC
authors.lastname: Zelarayan
authors.forename: Maike
authors.initials: M
authors.lastname: Hassenpflug
authors.forename: Karl
authors.initials: K
authors.lastname: Toischer
authors.forename: Hugo
authors.initials: H
authors.lastname: Sanchez-Ruderisch
authors.forename: Gerd
authors.initials: G
authors.lastname: Hasenfuss
authors.forename: Martin W
authors.initials: MW
authors.lastname: Bergmann
authors.forename: Hubertus
authors.initials: H
authors.lastname: Jarry
authors.forename: Vera
authors.initials: V
authors.lastname: Regitz-Zagrosek
mesh_terms: D000818:Animals; D016000:Cluster Analysis; D004958:Estradiol / Q000494:pharmacology*; D004967:Estrogens / Q000494:pharmacology; D005260:Female; D063990:Gene Ontology; D053263:Gene Regulatory Networks; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000254:growth & development; D015151:Immunoblotting; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010052:Ovariectomy; D010766:Phosphorylation / Q000187:drug effects; D059467:Transcriptome / Q000187:drug effects / Q000235:genetics; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D004967:Estrogens; D051176:beta Catenin; D004958:Estradiol; D038362:Glycogen Synthase Kinase 3