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Regulation of Mitogen‐Activated Protein Kinase and Down‐Stream Signaling by Guanylyl Cyclase‐A/Natriuretic Peptide Receptor‐A
Author(s) -
Tripathi Satyabha,
Kimonis Katerina O.,
Vellaichamy Elangovan,
Pandey Kailash N.
Publication year - 2008
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.22.1_supplement.645.3
Subject(s) - creb , atrial natriuretic peptide , protein kinase a , npr2 , medicine , npr1 , kinase , endocrinology , natriuretic peptide , signal transduction , phosphorylation , soluble guanylyl cyclase , chemistry , transcription factor , receptor , biology , microbiology and biotechnology , biochemistry , heart failure , gene , guanylate cyclase
Atrial natriuretic peptide (ANP) is a member of the natriuretic peptide hormone family that maintains cardiovascular homeostasis and exerts antiproliferative effects in a variety of cell types. ANP mediates its effects by binding guanylyl cyclase‐A/natriuretic peptide receptor‐A (GC‐A/NPRA) and subsequently activating cGMP‐dependent protein kinase (PKG), but the signaling pathways regulated by this system have not yet been elucidated. The objective of this study was to determine the effects of ANP‐NPRA system on mitogen‐activated protein kinases (MAPKs) and proliferative transcription factors AP‐1 and CREB in murine Leydig tumor (MA‐10) cells. Measurement of phorphorylated protein levels by Western blot demonstrated that vascular endothelial growth factor (VEGF) treatment caused a 3‐ to 4‐fold increase in phosphorylation of MAPKs (Erk1, Erk2, JNK, and p38). ANP treatment inhibited VEGF‐stimulated phosphorylation of MAPKs by 50–65%. VEGF treatment caused a 3‐ to 5‐fold increase in c‐jun, c‐fos, and CREB protein levels, an effect which was significantly inhibited by ANP treatment. ANP treatment inhibited VEGF‐stimulated AP‐1 and CREB transcriptional activity by 60–70% in a PKG‐dependent manner. Thus, the present study delineates that ANP/NPRA signaling can exert an inhibitory effect on the proliferative cellular mechanisms that play a critical role in angiogenic response in disease states.