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.

NT-proBNP as a predictor of death and cardiovascular events in patients with type 2 diabetes

“…There are three main biologically active NP: atrial NP (ANP), brain NP (currently called B-type NP, BNP) and C-type NP (CNP) [ 15 ]. Under normal conditions, the main sites of synthesis and secretion of ANP and BNP are the cardiac atria.…”

“…However, in pathological states, the ventricles start to produce and release higher concentrations of BNP. Although ANP are 50-fold greater, under physiological conditions, BNP has intensely more pronounced activity and, under pathological conditions, its plasma concentrations become 5–10 times greater than that of ANP [ 15 ]. ANP and BNP preferentially bind to the NP receptor A (NPRA).…”

“…ANP and BNP preferentially bind to the NP receptor A (NPRA). All three NP—ANP, BNP, and CNP—can bind to the NP receptor C (NPRC), which, because it lacks a catalytic domain of guanylyl cyclase, works as an NP scavenging receptor [ 15 ]. Binding of ANP and BNP to NPRA produces intracellular second messenger cyclic guanosine monophosphate which activates effector molecules such as cGMP-dependent protein kinase, gated ion channels, and phosphodiesterases to induce physiological actions in target tissues, including salt and water excretion, vasodilation, anti-inflammation, anti-hypertrophy, anti-fibrosis, anti-apoptosis, immunosuppressive responses and inhibition of the renin–angiotensin–aldosterone system (RAAS) [ 16 ].…”

“…Binding of ANP and BNP to NPRA produces intracellular second messenger cyclic guanosine monophosphate which activates effector molecules such as cGMP-dependent protein kinase, gated ion channels, and phosphodiesterases to induce physiological actions in target tissues, including salt and water excretion, vasodilation, anti-inflammation, anti-hypertrophy, anti-fibrosis, anti-apoptosis, immunosuppressive responses and inhibition of the renin–angiotensin–aldosterone system (RAAS) [ 16 ]. CNP is an autocrine and paracrine mediator released by endothelial cells and binds to the NP receptor B (NPRB) [ 15 ]. CNP acts predominantly on the endothelium playing a significant role in vascular homeostasis and may influence coronary circulation, and blood pressure, in addition to actions on the central nervous system and bone growth [ 17 ].…”

“…BNP has a longer half-life (12 to 20 min) than ANP (0.5 to 4 min) and exhibits more pronounced natriuretic and diuretic effects [ 15 ]. CNP, in turn, has very low plasma concentrations and a short half-life (2 to 3 min) [ 15 ].…”