Inhibitory Effect of C-Type Natriuretic Peptide (CNP) on Cultured Cardiac Myocyte Hypertrophy: Interference between CNP and Endothelin-1 Signaling Pathways

C-type natriuretic peptide (CNP) is known to play a role in the local regulation of vascular tone. We recently found that CNP is also produced by cardiac ventricular cells. However, its local effect on myocyte hypertrophy remains to be elucidated. The present study investigated the effects of CNP on...

Full description

Saved in:
Bibliographic Details
Published in:Endocrinology (Philadelphia) 2004-05, Vol.145 (5), p.2131-2140
Main Authors: Tokudome, Takeshi, Horio, Takeshi, Soeki, Takeshi, Mori, Kenji, Kishimoto, Ichiro, Suga, Shin-ichi, Yoshihara, Fumiki, Kawano, Yuhei, Kohno, Masakazu, Kangawa, Kenji
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Calcium - metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cardiomegaly
Cells, Cultured
Cyclic GMP - analogs & derivatives
Cyclic GMP - metabolism
Cyclic GMP - pharmacology
DNA - metabolism
DNA-Binding Proteins - metabolism
Drug Interactions
Endothelin-1 - pharmacology
Fundamental and applied biological sciences. Psychology
GATA4 Transcription Factor
MEF2 Transcription Factors
Mitogen-Activated Protein Kinases - metabolism
Myocardium - cytology
Myogenic Regulatory Factors
Natriuretic Peptide, C-Type - pharmacology
Phosphorylation
Rats
Rats, Wistar
Signal Transduction
Transcription Factors - metabolism
Vertebrates: endocrinology
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:C-type natriuretic peptide (CNP) is known to play a role in the local regulation of vascular tone. We recently found that CNP is also produced by cardiac ventricular cells. However, its local effect on myocyte hypertrophy remains to be elucidated. The present study investigated the effects of CNP on cultured cardiac myocyte hypertrophy and the interaction between CNP and endothelin-1 (ET-1) signaling pathways. CNP attenuated basal and ET-1-augumented protein synthesis, atrial natriuretic peptide secretion, hypertrophy-related gene expression, GATA-4 and MEF-2 DNA binding activities, Ca2+/calmodulin-dependent kinase II activity, and ERK phosphorylation. CNP also inhibited ET-1-induced increase in intracellular Ca2+ concentration. These effects of CNP were mimicked by a cGMP analog, 8-bromo cGMP. However, the inhibitory effects of CNP on the hypertrophic response of myocytes were significantly diminished at high concentrations of ET-1. Although CNP increased intracellular cGMP levels in myocytes, ET-1 suppressed CNP-induced cellular cGMP accumulation. A protein kinase C activator and Ca2+ ionophore mimicked this suppressive effect of ET-1. We further examined the effect of CNP on the paracrine action of ET-1 secreted from cardiac nonmyocytes. CNP and 8-bromo cGMP significantly inhibited ET-1 secretion from nonmyocytes. Although nonmyocyte-conditioned medium increased the protein synthesis in myocytes through endogenous ET-1 action, this increase was significantly attenuated by pretreatment of nonmyocytes with CNP and 8-bromo cGMP. These findings demonstrate that CNP inhibits ET-1-induced cardiac myocyte hypertrophy via a cGMP-dependent mechanism, and conversely, ET-1 inhibits CNP signaling by a protein kinase C- and Ca2+-dependent mechanism, suggesting mutual interference between CNP and ET-1 signaling pathways.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2003-1260