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.

Temporal cohesion of the structural, functional and molecular characteristics of the developing zebrafish heart

“…These two phases represent periods of significant structural change. The first phase between 48 and 72 hpf, similar to a previous report (Grimes et al, 2008) represents an increase in the cellular layering of the wall of the ventricle chamber while the second, between 96 and 120 hpf represents the newly forming trabecular network within the primitive ventricular cavity (Becker et al, 2014). Multinuclear cardiomyocytes are most observed at 72 and 96 hpf, although there was no clear pattern to the location of the cell divisions.…”

Dephosphorylation and inactivation of NPR2 guanylyl cyclase in granulosa cells contributes to the LH-induced decrease in cGMP that causes resumption of meiosis in rat oocytes

“…In particular, bone growth is affected by mutations in Npr2 or the Nppc gene that encodes CNP; increased NPR2 activity results in longer bones, whereas decreased activity results in shorter bones (Chusho et al, 2001;Tamura et al, 2004;Yasoda et al, 2004;Olney, 2006;Miura et al, 2012;Geister et al, 2013). Natriuretic peptide receptors also function in the development of the nervous system (Ter-Avetisyan et al, 2014) and heart (Becker et al, 2014). Some of the actions of growth factors and hormones that affect chondrocyte differentiation, axon bifurcation and cardiomyocyte proliferation might involve the regulation of natriuretic peptide receptor phosphorylation and/or levels of natriuretic peptides, as seen for LH-mediated regulation of meiosis in the ovary.…”

Puerarin Exerts a Delayed Inhibitory Effect on the Proliferation of Cardiomyocytes Derived from Murine ES Cells via Slowing Progression through G2/M Phase

“…Contemporary studies mostly focus on the mechanisms regulating cell cycle activity of CMs in vitro and in vivo, which are significant for the cardiovascular regenerative medicine community. Humoral factors have been shown to upregulate CM proliferation via critical signaling pathways, such as PI3K [13,14], ERK [14], Npr3 and cAMP [15], and JAK/STAT [16] signaling pathways. In neonatal rat CMs, nuclear import of Cyclin D1 and cyclin-dependent kinase 4 (Cdk4) stimulates proliferation by activating the retinoblastoma regulatory pathway [17].…”