Atrial natriuretic peptide suppresses endothelin gene expression and proliferation in cardiac fibroblasts through a GATA4-dependent mechanism.
Cardiovasc Res
; 84(2): 209-17, 2009 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-19546173
ABSTRACT
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 ANDRESULTS:
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-serine(105) 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.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Fator Natriurético Atrial
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Endotelina-1
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Miócitos Cardíacos
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Proliferação de Células
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Fator de Transcrição GATA4
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Fibroblastos
Tipo de estudo:
Prognostic_studies
Idioma:
En
Revista:
Cardiovasc Res
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Estados Unidos