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


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.


CONCLUSIONS
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.
Institute of Gender in Medicine , Charite-Universitaetsmedizin Berlin, Hessische Str. 3-4, 10115 Berlin, Germany.
Shokoufeh
S
Mahmoodzadeh
Elke
E
Dworatzek
Stephan
S
Fritschka
Thi Hang
TH
Pham
Vera
V
Regitz-Zagrosek
D000818:Animals; D002460:Cell Line; D004958:Estradiol / Q000378:metabolism* / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000235:genetics*; D061965:Matrix Metalloproteinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D020257:Ventricular Remodeling / Q000502:physiology; D050807:ets-Domain Protein Elk-1 / Q000378:metabolism
D047628:Estrogen Receptor alpha; D004967:Estrogens; D061965:Matrix Metalloproteinase Inhibitors; D012333:RNA, Messenger; D050807:ets-Domain Protein Elk-1; D004958:Estradiol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020778:Matrix Metalloproteinase 2