title: Estrogen receptor-beta signals left ventricular hypertrophy sex differences in normotensive deoxycorticosterone acetate-salt mice.
abstract: We found earlier that deoxycorticosterone acetate-salt treatment causes blood pressure-independent left ventricular hypertrophy, but only in male mice. To test the hypothesis that the estrogen receptor-β (ERβ) protects the females from left ventricular hypertrophy, we treated male and female ERβ-deficient (ERβ(-/-)) mice and their male and female littermates (wild-type [WT]) with deoxycorticosterone acetate-salt and made them telemetrically normotensive with hydralazine. WT males had increased (+16%) heart weight/tibia length ratios compared with WT females (+7%) at 6 weeks. In ERβ(-/-) mice, this situation was reversed. Female WT mice had the greatest heart weight/tibia length ratio increases of all of the groups (+23%), even greater than ERβ(-/-) males (+10%). Echocardiography revealed concentric left ventricular hypertrophy in male WT mice, whereas ERβ(-/-) females developed dilative left ventricular hypertrophy. The hypertrophic response in female ERβ(-/-) mice was accompanied by the highest degree of collagen deposition, indicating maladaptive remodeling. ERβ(+/+) females showed robust protective p38 and extracellular signal-regulated kinase 1/2 signaling relationships compared with other groups. Calcineurin Aβ expression and its positive regulator myocyte-enriched calcineurin-interacting protein 1 were increased in deoxycorticosterone acetate-salt female ERβ(-/-) mice, yet lower than in WT males. Endothelin increased murine cardiomyocyte hypertrophy in vitro, which could be blocked by estradiol and an ERβ agonist. We conclude that a functional ERβ is essential for inducing adaptive p38 and extracellular signal-regulated kinase signaling, while reducing maladaptive calcineurin signaling in normotensive deoxycorticosterone acetate female mice. Our findings address the possibility of sex-specific cardiovascular therapies.
authors.affiliation: Department of Nephrology and Intensive Care Medicine Campus Virchow-Klinikum, Center forCardiovascular Research Medical Faculty, Charite´ Berlin, Berlin, Germany.
authors.forename: Dennis
authors.initials: D
authors.lastname: Gürgen
authors.forename: Björn
authors.initials: B
authors.lastname: Hegner
authors.forename: Angelika
authors.initials: A
authors.lastname: Kusch
authors.forename: Rusan
authors.initials: R
authors.lastname: Catar
authors.forename: Lyubov
authors.initials: L
authors.lastname: Chaykovska
authors.forename: Uwe
authors.initials: U
authors.lastname: Hoff
authors.forename: Volkmar
authors.initials: V
authors.lastname: Gross
authors.forename: Torsten
authors.initials: T
authors.lastname: Slowinski
authors.forename: Andrey C
authors.initials: AC
authors.lastname: da Costa Goncalves
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kintscher
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Duska
authors.initials: D
authors.lastname: Dragun
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D003900:Desoxycorticosterone / Q000494:pharmacology*; D004452:Echocardiography; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D005434:Flow Cytometry; D006830:Hydralazine / Q000494:pharmacology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000000981:diagnostic imaging / Q000378:metabolism*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008901:Mineralocorticoids / Q000494:pharmacology*; D009206:Myocardium / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012727:Sex Characteristics; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D047629:Estrogen Receptor beta; D008901:Mineralocorticoids; D006830:Hydralazine; D003900:Desoxycorticosterone