The Impact of Natriuretic Peptides on Heart Development, Homeostasis, and Disease

Abstract

During mammalian heart development, the clustered genes encoding peptide hormones, Natriuretic Peptide A (NPPA; ANP) and B (NPPB; BNP), are transcriptionally co-regulated and co-expressed predominately in the atrial and ventricular trabecular cardiomyocytes. After birth, expression of NPPA and a natural antisense transcript NPPA-AS1 becomes restricted to the atrial cardiomyocytes. Both NPPA and NPPB are induced by cardiac stress and serve as markers for cardiovascular dysfunction or injury. NPPB gene products are extensively used as diagnostic and prognostic biomarkers for various cardiovascular disorders. Membrane-localized guanylyl cyclase receptors on many cell types throughout the body mediate the signaling of the natriuretic peptide ligands through the generation of intracellular cGMP, which interacts with and modulates the activity of cGMP-activated kinase and other enzymes and ion channels. The natriuretic peptide system plays a fundamental role in cardio-renal homeostasis, and its potent diuretic and vasodilatory effects provide compensatory mechanisms in cardiac pathophysiological conditions and heart failure. In addition, both peptides, but also CNP, have important intracardiac actions during heart development and homeostasis independent of the systemic functions. Exploration of the intracardiac functions may provide new leads for the therapeutic utility of natriuretic peptide-mediated signaling in heart diseases and rhythm disorders. Here, we review recent insights into the regulation of expression and intracardiac functions of NPPA and NPPB during heart development, homeostasis, and disease.

Keywords: cardiac disease; cardiac homeostasis; heart development; natriuretic peptides.

Figure 1

Overview of epigenetic regulation of Nppa and Nppb (A) RNA-seq, H3K27ac, EMERGE, and ATAC-seq in the left ventricle (LV) and the border zone (BZ). (B) Overview of epigenetic state changes at the Nppb, Nppa/Nppa-as locus in healthy ventricles and left ventricular border zone 7 days after MI (see [64,72] for source data). (C) Overview of the proposed mechanisms of Nppa-as-mediated Nppa regulation.

Figure 2

Overview of NP signaling pathways in CMs or involved in crosstalk between cells in the heart. Black arrows; downstream activation, small black arrows; increase or decrease of an effector, grey arrows; underlying mechanistic pathways have not yet been described.