title: Atrial natriuretic peptide inhibits cell cycle activity of embryonic cardiac progenitor cells via its NPRA receptor signaling axis.
abstract: The biological effects of atrial natriuretic peptide (ANP) are mediated by natriuretic peptide receptors (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 receptor-specific 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.
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Adam
authors: A
authors: Hotchkiss
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Tiam
authors: T
authors: Feridooni
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Mark
authors: M
authors: Baguma-Nibasheka
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Kathleen
authors: K
authors: McNeil
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors: Sarita
authors: S
authors: Chinni
authors: Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada kpasumar@dal.ca.
authors: Kishore B S
authors: KB
authors: Pasumarthi
mesh_terms: D000818:Animals; D009320:Atrial Natriuretic Factor / Q000096:biosynthesis* / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D009320:Atrial Natriuretic Factor; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A
keywords: ANP; cardiac progenitor cells; cardiomyocytes; cell proliferation and differentiation; embryonic heart; gene expression; knockin mice; lineage tracking; natriuretic peptide receptors