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Cardiovascular Research Advance Access [Accepted Manuscript] published online on June 22, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp208
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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.

ANP SUPPRESSES ENDOTHELIN GENE EXPRESSION AND PROLIFERATION IN CARDIAC FIBROBLASTS THROUGH A GATA4 DEPENDENT MECHANISM

Denis J. Glenn*,+, Dolkun Rahmutula*,+, Minobu Nishimoto, Faquan Liang and David G. Gardner*

Diabetes Center
* Department of Medicine, University of California at San Francisco, San Francisco, CA

Address correspondence to: David G. Gardner, 1109 HSW, Diabetes Center, UCSF, 513 Parnassus Ave, San Francisco, CA 94143-0540, Tel (415)-476-2729, Fax (415) 564-5813, Email: 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 atrial natriuretic peptide inhibits endothelin 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 endothelin 1 (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-Serine 105GATA4 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 neighboring 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

+ Contributed equally to this work

Abbreviated Title: ANP inhibits ET-1 Expression in Fibroblasts


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