title: Estrogen attenuates left ventricular and cardiomyocyte hypertrophy by an estrogen receptor-dependent pathway that increases calcineurin degradation.
abstract: Left ventricular (LV) hypertrophy commonly develops in response to chronic hypertension and is a significant risk factor for heart failure and death. The serine-threonine phosphatase calcineurin (Cn)A plays a critical role in the development of pathological hypertrophy. Previous experimental studies in murine models show that estrogen limits pressure overload-induced hypertrophy; our purpose was to explore further the mechanisms underlying this estrogen effect. Wild-type, ovariectomized female mice were treated with placebo or 17beta-estradiol (E2), followed by transverse aortic constriction (TAC), to induce pressure overload. At 2 weeks, mice underwent physiological evaluation, immediate tissue harvest, or dispersion of cardiomyocytes. E2 replacement limited TAC-induced LV and cardiomyocyte hypertrophy while attenuating deterioration in LV systolic function and contractility. These E2 effects were associated with reduced abundance of CnA. The primary downstream targets of CnA are the nuclear factor of activated T-cell (NFAT) family of transcription factors. In transgenic mice expressing a NFAT-activated promoter/luciferase reporter gene, E2 limited TAC-induced activation of NFAT. Moreover, the inhibitory effects of E2 on LV hypertrophy were absent in CnA knockout mice, supporting the notion that CnA is an important target of E2-mediated inhibition. In cultured rat cardiac myocytes, E2 inhibited agonist-induced hypertrophy while also decreasing CnA abundance and NFAT activation. Agonist stimulation also reduced CnA ubiquitination and degradation that was prevented by E2; all in vitro effects of estrogen were reversed by an estrogen receptor (ER) antagonist. These data support that E2 reduces pressure overload induced hypertrophy by an ER-dependent mechanism that increases CnA degradation, unveiling a novel mechanism by which E2 and ERs regulate pathological LV and cardiomyocyte growth.
authors.affiliation: Molecular Cardiology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA.
authors.forename: Cameron
authors.initials: C
authors.lastname: Donaldson
authors.forename: Sarah
authors.initials: S
authors.lastname: Eder
authors.forename: Corey
authors.initials: C
authors.lastname: Baker
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Aronovitz
authors.forename: Alexandra Dabreo
authors.initials: AD
authors.lastname: Weiss
authors.forename: Monica
authors.initials: M
authors.lastname: Hall-Porter
authors.forename: Feng
authors.initials: F
authors.lastname: Wang
authors.forename: Adam
authors.initials: A
authors.lastname: Ackerman
authors.forename: Richard H
authors.initials: RH
authors.lastname: Karas
authors.forename: Jeffery D
authors.initials: JD
authors.lastname: Molkentin
authors.forename: Richard D
authors.initials: RD
authors.lastname: Patten
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019703:Calcineurin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004343:Drug Implants; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D000077267:Fulvestrant; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010052:Ovariectomy; D010656:Phenylephrine / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling
chemical_list: D004343:Drug Implants; D004965:Estrogen Antagonists; D050778:NFATC Transcription Factors; D011960:Receptors, Estrogen; D025801:Ubiquitin; D010656:Phenylephrine; D000077267:Fulvestrant; D004958:Estradiol; D019703:Calcineurin; D046988:Proteasome Endopeptidase Complex