title: Inhibitory effect of C-type natriuretic peptide (CNP) on cultured cardiac myocyte hypertrophy: interference between CNP and endothelin-1 signaling pathways.
abstract: 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, Ca(2+)/calmodulin-dependent kinase II activity, and ERK phosphorylation. CNP also inhibited ET-1-induced increase in intracellular Ca(2+) 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 Ca(2+) 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 Ca(2+)-dependent mechanism, suggesting mutual interference between CNP and ET-1 signaling pathways.
authors.affiliation: Research Institute, National Cardiovascular Center, Suita, Osaka 565-8565, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokudome
authors.forename: Takeshi
authors.initials: T
authors.lastname: Horio
authors.forename: Takeshi
authors.initials: T
authors.lastname: Soeki
authors.forename: Kenji
authors.initials: K
authors.lastname: Mori
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kishimoto
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Suga
authors.forename: Fumiki
authors.initials: F
authors.lastname: Yoshihara
authors.forename: Yuhei
authors.initials: Y
authors.lastname: Kawano
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D006332:Cardiomegaly; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D050991:GATA4 Transcription Factor; D064326:MEF2 Transcription Factors; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D018006:Myogenic Regulatory Factors; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D019332:Endothelin-1; D050991:GATA4 Transcription Factor; D064326:MEF2 Transcription Factors; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors; D020098:Natriuretic Peptide, C-Type; C016276:8-bromocyclic GMP; D004247:DNA; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D006152:Cyclic GMP; D002118:Calcium