title: 17beta-estradiol antagonizes cardiomyocyte hypertrophy by autocrine/paracrine stimulation of a guanylyl cyclase A receptor-cyclic guanosine monophosphate-dependent protein kinase pathway.
abstract: BACKGROUND
  Significant gender-related differences exist in the development of left ventricular hypertrophy (LVH). In addition, administration of 17beta-estradiol (E2) to ovariectomized female mice attenuates the development of LVH, demonstrating an antagonistic role for E2 in this process, although no molecular mechanism has been proposed for this phenomenon.
  
  
  RESULTS
  E2 attenuated phenylephrine and endothelin-1 induced hypertrophy in neonatal cardiomyocytes, and E2 directly induced atrial natriuretic factor (ANF) expression as assessed by Northern blot, immunocytochemical analyses, and transient transfection assays using ANF promoter deletion fragments. Both the antihypertrophic effects and ANF induction could be blocked by the estrogen receptor antagonist ICI 182,780, which demonstrates a genomic, estrogen receptor-dependent pathway. To mimic E2-induced autocrine/paracrine effects through stimulation of the guanylyl cyclase A receptor (ANF receptor), cardiomyocytes were stimulated with phenylephrine or endothelin-1 in the presence of exogenous ANF or 8-bromo-cyclic guanosine monophosphate (cGMP), both of which attenuated agonist-induced hypertrophy. Both estrogen and ANF increased cGMP activity. The antihypertrophic effect of ANF could be reduced with extracellular ANF antibodies in a dose-dependent manner. cGMP-dependent protein kinase mediates the antihypertrophic effects of E2, so cardiomyocytes were agonist stimulated in the presence of the cGMP-dependent protein kinase blocker KT-5823. KT-5823 not only reversed the antihypertrophic properties of E2, ANF, or 8-bromo-cGMP, but also evoked potentiation of hypertrophy.
  
  
  CONCLUSIONS
  E2-mediated induction of ANF in cardiac hypertrophy contributes to its antagonistic effects in LVH.
authors.affiliation: Department of Cardiology, Cardiovascular Research Institute Maastricht, The Netherlands.
authors.forename: Fawzi A
authors.initials: FA
authors.lastname: Babiker
authors.forename: Leon J
authors.initials: LJ
authors.lastname: De Windt
authors.forename: Martin
authors.initials: M
authors.lastname: van Eickels
authors.forename: Victor
authors.initials: V
authors.lastname: Thijssen
authors.forename: Ronald J P
authors.initials: RJ
authors.lastname: Bronsaer
authors.forename: Christian
authors.initials: C
authors.lastname: Grohé
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D019898:Autocrine Communication; D002460:Cell Line; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000378:metabolism*; D006352:Heart Ventricles / Q000166:cytology; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000209:etiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019899:Paracrine Communication; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011917:Rats, Inbred Lew; D017461:Receptors, Atrial Natriuretic Factor / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004958:Estradiol; D009320:Atrial Natriuretic Factor; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A