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(Circulation. 2004;109:269-276.)
© 2004 American Heart Association, Inc.

Basic Science Reports

17ß-Estradiol Antagonizes Cardiomyocyte Hypertrophy by Autocrine/Paracrine Stimulation of a Guanylyl Cyclase A Receptor-Cyclic Guanosine Monophosphate-Dependent Protein Kinase Pathway

Fawzi A. Babiker, MS; Leon J. De Windt, PhD; Martin van Eickels, MD; Victor Thijssen, PhD; Ronald J.P. Bronsaer, MS; Christian Grohé, MD; Marc van Bilsen, PhD; Pieter A. Doevendans, MD, PhD

From the Departments of Cardiology (F.A.B., V.T., R.J.P.B.) and Physiology (M.v.B.), Cardiovascular Research Institute Maastricht, the Hubrecht Laboratory (L.J.D., P.A.D.), Utrecht, and the Department of Cardiology (P.A.D.), Heart-Lung Center Utrecht and Interuniversity Cardiology Institute Netherlands; and the Medizinische Universität-Poliklinik, University of Bonn, Germany (M.v.E., C.G.).

Correspondence to Pieter A. Doevendans, Department of Cardiology, HLCU, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands. E-mail p.doevendans{at}hli.azu.nl

Received January 21, 2003; de novo received July 15, 2003; revision received September 4, 2003; accepted September 8, 2003.

Background— Significant gender-related differences exist in the development of left ventricular hypertrophy (LVH). In addition, administration of 17ß-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.

Methods and 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.

Key Words: hypertrophy • remodeling • cells • genes

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