Cardiovascular Research Advance Access originally published online on June 22, 2009
Cardiovascular Research 2009 84(2):209-217; doi:10.1093/cvr/cvp208
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Atrial natriuretic peptide suppresses endothelin gene expression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism
1 Department of Medicine, University of California at San Francisco, San Francisco, CA, USA
2 Diabetes Center, University of California at San Francisco, 1109 HSW, 513 Parnassus Ave., San Francisco, CA 94143-0540, USA
* Corresponding author. Tel +1 415 476 2729; fax: +1 415 564 5813. E-mail address: dgardner{at}diabetes.ucsf.edu
Aims: Atrial natriuretic peptide (ANP) is a hormone that has both antihypertrophic and antifibrotic properties in the heart. We hypothesized that myocyte-derived ANP inhibits endothelin (ET) gene expression in fibroblasts.
Methods and results: We have investigated the mechanism(s) involved in the antiproliferative effect of ANP on cardiac fibroblasts in a cell culture model. We found that cardiac myocytes inhibited DNA synthesis in co-cultured cardiac fibroblasts as did treatment with the ET-1 antagonist BQ610. The effect of co-culture was reversed by antibody directed against ANP or the ANP receptor antagonist HS-142-1. ANP inhibited the expression of the ET-1 gene and ET-1 gene promoter activity in cultured fibroblasts. The site of the inhibition was localized to a GATA-binding site positioned between –132 and –135 upstream from the transcription start site. GATA4 expression was demonstrated in cardiac fibroblasts, GATA4 bound the ET-1 promoter both in vitro and in vivo, and siRNA-mediated knockdown of GATA4 inhibited ET-1 expression. ET-1 treatment resulted in increased levels of phospho-serine105 GATA4 in cardiac fibroblasts and this induction was partially suppressed by co-treatment with ANP.
Conclusion: Collectively, these findings suggest that locally produced ET-1 serves as an autocrine stimulator of fibroblast proliferation, that ANP produced in neighbouring myocytes serves as a paracrine inhibitor of this proliferation, and that the latter effect operates through a reduction in GATA4 phosphorylation and coincident reduction in GATA4-dependent transcriptional activity.
KEYWORDS Cardiac fibroblasts; Atrial natriuretic peptide; Endothelin; GATA4
Time for primary review: 42 days
These authors contributed equally to this work.
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Cardiovasc Res 2009 84: 176-177.
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  M. Jankowski GATA4, a new regulator of cardiac fibroblasts, is sensitive to natriuretic peptides Cardiovasc Res, November 1, 2009; 84(2): 176 - 177. [Full Text] [PDF]
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