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Cardiovasc Res. 2010 Mar 1;85(4):719-28. doi: 10.1093/cvr/cvp350. Epub 2009 Oct 27.

17beta-Estradiol inhibits matrix metalloproteinase-2 transcription via MAP kinase in fibroblasts.

Author information

1
Institute of Gender in Medicine , Charite-Universitaetsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany.

Abstract

AIMS:

Female sex and sex hormones contribute to cardiac remodelling. 17beta-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/ERalpha-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.

PMID:
19861308
PMCID:
PMC2819834
DOI:
10.1093/cvr/cvp350
[Indexed for MEDLINE]
Free PMC Article
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