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Cardiovascular Research Advance Access first published online on October 27, 2009
This version [Corrected Proof] published online on November 19, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp350
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org
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17β-estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts

Shokoufeh Mahmoodzadeh1,2,{dagger}, Elke Dworatzek1,2,{dagger}, Stephan Fritschka1,2, Thi Hang Pham1,2 and Vera Regitz-Zagrosek1,2,3,*

1 Institute of Gender in Medicine (GiM), Charite-Universitaetsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany
2 Center for Cardiovascular Research (CCR), Charite-Universitaetsmedizin Berlin, Berlin, Germany
3 German Heart Institute Berlin (DHZB), Berlin, Germany

* Corresponding author. Tel: +49 30 450 525 172, Fax: +49 30 450 525 972, Email: vera.regitz-zagrosek{at}charite.de

Aims: Female sex and sex hormones contribute to cardiac remodelling. 17β-estradiol (E2) is involved in the modulation of extracellular matrix composition and function. Here, we analysed the effect of E2 on matrix metalloproteinase (MMP)-2 gene expression and studied the underlying molecular mechanisms in rat cardiac fibroblasts and in a human fibroblast cell line.

Methods and results: In adult rat cardiac fibroblasts, E2 significantly decreased MMP-2 gene expression in an estrogen receptor (ER)-dependent manner. Transient transfection experiments of human MMP-2 (hMMP-2) promoter deletion constructs in a human fibroblast cell line revealed a regulatory region between –324 and –260 bp that is involved in E2/ER{alpha}-mediated repression of hMMP-2 gene transcription. Electrophoretic mobility shift assays (EMSA) and supershift analysis demonstrated the binding of transcription factor Elk-1 within this promoter region. Elk-1 was phosphorylated by E2 via the mitogen-activated protein kinase (MAPK) signalling pathway as shown by western blotting. Treatment of cells with the MAPK inhibitor PD98059 blocked the E2-dependent repression of hMMP-2 promoter activity as well as the endogenous MMP-2 mRNA levels in both human fibroblast cells and rat cardiac fibroblasts.

Conclusion: E2 inhibits MMP-2 expression via the ER and the MAPK pathway in rat cardiac fibroblasts and in a human fibroblast cell line. These mechanisms may contribute to sex-specific differences in fibrotic processes that are observed in human heart and other diseases.

KEYWORDS MMP-2; Gene expression; Estrogen; Cardiac fibroblasts; ER{alpha}; Elk-1

Time for primary review: 23 days

{dagger} Both authors contributed equally to this work.


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