Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis

Abstract

(NPRs), which can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. During cardiac development, ANP serves as an early maker of differentiating atrial and ventricular chamber myocardium. As development proceeds, expression of ANP persists in the atria but declines in the ventricles. Currently, it is not known whether ANP is secreted or the ANP-NPR signaling system plays any active role in the developing ventricles. Thus the primary aims of this study were to 1) examine biological activity of ANP signaling systems in embryonic ventricular myocardium, and 2) determine whether ANP signaling modulates proliferation/differentiation of undifferentiated cardiac progenitor cells (CPCs) and/or cardiomyocytes. Here, we provide evidence that ANP synthesized in embryonic day (E)11.5 ventricular myocytes is actively secreted and processed to its biologically active form. Notably, NPRA and NPRC were detected in E11.5 ventricles and exogenous ANP stimulated production of cGMP in ventricular cell cultures. Furthermore, we showed that exogenous ANP significantly decreased cell number and DNA synthesis of CPCs but not cardiomyocytes and this effect could be reversed by pretreatment with the NPRA receptorspecific inhibitor A71915. ANP treatment also led to a robust increase in nuclear p27 levels in CPCs compared with cardiomyocytes. Collectively, these data provide evidence that in the developing mammalian ventricles ANP plays a local paracrine role in regulating the balance between CPC proliferation and differentiation via NPRA/ cGMP-mediated signaling pathways. embryonic heart; ANP; natriuretic peptide receptors; gene expression; cardiac progenitor cells; cardiomyocytes; lineage tracking; knockin mice; cell proliferation and differentiation ATRIAL NATRIURETIC PEPTIDE (ANP) is a 28 amino acid peptide that is synthesized and stored primarily in secretory granules of atrial cardiomyocytes in the adult heart. Ligand binding of ANP to its cognate natriuretic peptide receptors (NPRs) can either activate guanylyl cyclase (NPRA and NPRB) or inhibit adenylyl cyclase (NPRC) to modulate intracellular cGMP or cAMP, respectively. The primary stimulus for ANP secretion from atrial cardiomyocytes is mechanical stretch of the atrial wall (15). In addition to mechanical stimuli, several vasoconstrictor peptides including endothelin-1 (ET-1) (36) and angiotensin II (9), as well as a variety of neurohormones, growth factors, and cytokines, have been shown to modulate natriuretic peptide secretion (10). Once in the circulation, ANP acts in a true endocrine fashion by stimulating NPRA receptors in the kidneys, adrenal cortex, and vasculature to regulate fluid homeostasis and maintain blood pressure via diuretic, natriuretic and vasorelaxant effects (29). In the ventricles of the adult heart, the levels of ANP protein are normally ϳ1,000-fold lower than in the atria and secretory granules are rarely observed (31).In contrast to the adult heart, developmental stud...

Atrial natriuretic peptide regulates adipose tissue accumulation in adult atria

“…These studies notably reported activation of guanylyl cyclase-B by C-type natriuretic peptide or the inhibition of PDEs using 3-isobutyl-1-methylxanthine (IBMX) (45,46). Furthermore, during embryonic development, the regulation by the NPRA/ cGMP signaling pathway of the balance between proliferation and differentiation of cardiac progenitor cells is essential for cardiac growth (47). Therefore, the NPRA/cGMP signaling pathway appears to be a critical regulatory node for the effect of ANP on cardiac tissue homeostasis.…”

ANP promotes proliferation and inhibits apoptosis of ovarian granulosa cells by NPRA/PGRMC1/EGFR complex and improves ovary functions of PCOS rats

“…ANP and NPRA were involved in the fertilization process. Hotchkiss et al 35 found that NPRA was expressed on blastocysts and embryonic stem cells, and involved in maintaining embryonic stem cells self-renewal and pluripotency. Zhang et al 36 also reported that the binding of ANP and NPRA induced sperm acrosome reaction occurred, whereas the receptor antagonist could eliminate the effect of ANP.…”

The therapeutic effect of B‐type natriuretic peptides in acute decompensated heart failure

“…There are a myriad of experimental data describing the role of NPs and their receptors in cell signalling. Hotchkiss et al 79 aimed to evaluate the biological role of ANP signalling systems in embryonic ventricular myocardium. The authors identified local paracrine activity of ANP in the regulation of the balance between cardiac progenitor cell proliferation and differentiation through NPR‐A/cGMP‐mediated signalling pathways in the processes of developing mammalian ventricles 79 .…”

“…Hotchkiss et al 79 aimed to evaluate the biological role of ANP signalling systems in embryonic ventricular myocardium. The authors identified local paracrine activity of ANP in the regulation of the balance between cardiac progenitor cell proliferation and differentiation through NPR‐A/cGMP‐mediated signalling pathways in the processes of developing mammalian ventricles 79 . The cGMP molecule is able to target several downstream signalling pathways including protein kinase G (PKG), phosphodiesterase 2 (PDE2) and phosphodiesterase 3 (PDE3).…”