title: Differential activation of natriuretic peptide receptors modulates cardiomyocyte proliferation during development.
abstract: Organ development is a highly regulated process involving the coordinated proliferation and differentiation of diverse cellular populations. The pathways regulating cell proliferation and their effects on organ growth are complex and for many organs incompletely understood. In all vertebrate species, the cardiac natriuretic peptides (ANP and BNP) are produced by cardiomyocytes in the developing heart. However, their role during cardiogenesis is not defined. Using the embryonic zebrafish and neonatal mammalian cardiomyocytes we explored the natriuretic peptide signaling network during myocardial development. We observed that the cardiac natriuretic peptides ANP and BNP and the guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2 are functionally redundant during early cardiovascular development. In addition, we demonstrate that low levels of the natriuretic peptides preferentially activate Npr3, a receptor with Gi activator sequences, and increase cardiomyocyte proliferation through inhibition of adenylate cyclase. Conversely, high concentrations of natriuretic peptides reduce cardiomyocyte proliferation through activation of the particulate guanylate cyclase-linked natriuretic peptide receptors Npr1 and Npr2, and activation of protein kinase G. These data link the cardiac natriuretic peptides in a complex hierarchy modulating cardiomyocyte numbers during development through opposing effects on cardiomyocyte proliferation mediated through distinct cyclic nucleotide signaling pathways.
authors.affiliation: Division of Cardiovascular Medicine, Vanderbilt University School of Medicine, Nashville, TN 37235, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Becker
authors.forename: Sneha
authors.initials: S
authors.lastname: Chatterjee
authors.forename: Tamara Y
authors.initials: TY
authors.lastname: Robinson
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: Bennett
authors.forename: Daniela
authors.initials: D
authors.lastname: Panáková
authors.forename: Cristi L
authors.initials: CL
authors.lastname: Galindo
authors.forename: Lin
authors.initials: L
authors.lastname: Zhong
authors.forename: Jordan T
authors.initials: JT
authors.lastname: Shin
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Coy
authors.forename: Amy E
authors.initials: AE
authors.lastname: Kelly
authors.forename: Dan M
authors.initials: DM
authors.lastname: Roden
authors.forename: Chee Chew
authors.initials: CC
authors.lastname: Lim
authors.forename: Calum A
authors.initials: CA
authors.lastname: MacRae
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D000242:Cyclic AMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006321:Heart / Q000196:embryology; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism*; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D029961:Zebrafish Proteins; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D000242:Cyclic AMP; D017869:Cyclic GMP-Dependent Protein Kinases; D017461:Receptors, Atrial Natriuretic Factor
keywords: ANP; BNP; Cardiomyocyte proliferation; Heart development; Natriuretic peptides; Npr3