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Repression of Proliferative Transcription Factors by Guanylyl Cyclase‐A/ Natriuretic Peptide Receptor‐A in Mouse Mesangial Cells
Author(s) -
Tripathi Satyabha,
Kumar Prerna,
Pandey Kailash N.
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.660.15
Subject(s) - creb , atrial natriuretic peptide , npr2 , npr1 , medicine , transcription factor , endocrinology , chromatin immunoprecipitation , chemistry , natriuretic peptide , signal transduction , receptor , angiotensin ii , microbiology and biotechnology , biology , gene expression , promoter , biochemistry , heart failure , gene
Atrial natriuretic peptide (ANP) is a member of the natriuretic peptide hormone family that maintains cardiovascular homeostasis and exerts antiproliferative effects on various cell types. ANP mediates its effects by binding guanylyl cyclase‐A/natriuretic peptide receptor‐A (GC‐A/NPRA) and activating cGMP‐dependent protein kinase (PKG). The objective of this study was to determine the effects of ANP‐NPRA system on the proliferative transcription factors activating protein‐1 (AP‐1) and cAMP‐response element binding protein (CREB) in mouse mesangial cells (MMCs). Treatment of MMCs with vascular endothelial growth factor (VEGF) stimulated phosphorylation of c‐jun, c‐fos, and CREB by 3‐ to 4‐ fold compared to control cells. ANP treatment significantly reduced VEGF‐stimulated AP‐1 and CREB transcriptional activity in a PKG‐dependent manner. Moreover, treatment of VEGF‐stimulated cells with ANP inhibited in vitro and in vivo binding of AP‐1 (c‐fos and c‐jun) and CREB to DNA, as measured by electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). The inhibitory effects of ANP were augmented by 60‐70% in NPRA‐transfected relative to vector‐transfected MMCs. The present study delineates a mechanism through which ANP‐NPRA signaling exerts an inhibitory effect on cell proliferation and plays a critical role in responses to cardiovascular disease states.