Molecular Signaling Mechanisms and Function of Natriuretic Peptide Receptor-A in the Pathophysiology of Cardiovascular Homeostasis

Abstract

The discovery of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP) and their cognate receptors has greatly increased our knowledge of the control of hypertension and cardiovascular homeostasis. ANP and BNP are potent endogenous hypotensive hormones that elicit natriuretic, diuretic, vasorelaxant, antihypertrophic, antiproliferative, and antiinflammatory effects, largely directed toward the reduction of blood pressure (BP) and cardiovascular diseases (CVDs). The principal receptor involved in the regulatory actions of ANP and BNP is guanylyl cyclase/natriuretic peptide receptor-A (GC-A/NPRA), which produces the intracellular second messenger cGMP. Cellular, biochemical, molecular, genetic, and clinical studies have facilitated understanding of the functional roles of natriuretic peptides (NPs), as well as the functions of their receptors, and signaling mechanisms in CVDs. Transgenic and gene-targeting (gene-knockout and gene-duplication) strategies have produced genetically altered novel mouse models and have advanced our knowledge of the importance of NPs and their receptors at physiological and pathophysiological levels in both normal and disease states. The current review describes the past and recent research on the cellular, molecular, genetic mechanisms and functional roles of the ANP-BNP/NPRA system in the physiology and pathophysiology of cardiovascular homeostasis as well as clinical and diagnostic markers of cardiac disorders and heart failure. However, the therapeutic potentials of NPs and their receptors for the diagnosis and treatment of cardiovascular diseases, including hypertension, heart failure, and stroke have just begun to be expanded. More in-depth investigations are needed in this field to extend the therapeutic use of NPs and their receptors to treat and prevent CVDs.

Keywords: cardiovascular disorders; gene-targeting; genetic mouse models; natriuretic peptide receptors; natriuretic peptides.

FIGURE 1

Ligand-binding specificity of different NPs (ANP, BNP, and CNP) with their cognate receptors (NPRA, NPRB, NPRC) and intracellular signaling mechanisms leading to the physiological responses. The diagram depicts that specific NP ligands activate their cognate receptor(s) and generate intracellular signals. The extracellular ligand binding domain (LBD) and intracellular protein kinase-like homology domain (protein-KHD) and guanylyl cyclase (GC) catalytic domain of GC-A/NPRA and GC-B/NPRB are shown. Both NPRA and NPRB produce intracellular second messenger cGMP, which activates effector molecules, including cGMP-dependent protein kinase (PKG), gated ion channels (CNG), and phosphodiesterase (PDE) to produce specific biological and physiological responsiveness.

FIGURE 2

The schematic representation of the NP-dependent activation and signaling of ANP/NPRA in the heart. To maintain the cardiac homeostasis, Npr1 gene is transcribed and translated to produce mature NPRA protein. Specifically, NPRA is activated by ANP and BNP; in turn produces intracellular second messenger cGMP that activates various physiological responsiveness in the heart tissues and cells.

FIGURE 3

Ablation of Npr1 triggers the activation of proinflammatory pathways that promotes cardiac hypertrophy, fibrosis, and remodeling. Disruption of ANP/NPRA signaling causes unbalanced activation of master transcription factor NF-κB that initiates the expression of proinflammatory cytokines and matrix proteins; thereby promotes specific cardiac structural and molecular changes in Npr1^–/– mice heart. The activated NF-κB translocates into the nucleus and promotes the genes transcription and expression of various proinflammatory cytokines and extracellular matrix proteins, including MMP-2 and MMP-9. Increased activation of NF-κB, thereby promotes medial thickening and perivascular fibrosis, in turn leads to the cardiac hypertrophy, fibrosis, remodeling and heart failure. On the other hand, the absence of ANP/NPRA signaling also simultaneously inhibits SERCA-2a that increases the cytosolic Ca2⁺ levels, thereby results in the increased contractile activity of the heart, which also promotes cardiac hypertrophy and remodeling. Ang II, angiotensin II; TGF-β1, transforming growth factor-β1; TNF-α, tumor necrosis factor-α; IKK, inhibitory kappa kinase; IKB, inhibitory kappa B, NF-κB, nuclear factor-kappa B; PKG, cGMP-dependent protein kinase; SERCA-2a, sarcolemmal endoplasmic reticulum Ca2⁺-ATPase-2a; MMP-2 and -9, matrix metalloproteinase-2 and −9.