Natriuretic peptides & B-type Natriuretic Peptides

By Nadezhda Glezeva PhD

General characteristics of the natriuretic peptide family

The natriuretic peptide (NP) family is a family of four structurally similar yet genetically distinct cardiac- and vascular-derived factors with diverse functions in the cardiovascular, renal and endocrine systems. Atrial NP (ANP) is the oldest and most studied member of the family since its discovery in rat atrial muscle extracts in 1981 [89]. The second best characterized peptide, brain or B-type NP (BNP) was initially purified from porcine brain extracts in 1988 [90]. Two years later, C-type NP (CNP) was identified in the porcine brain [91]. The last and newest member of the family, Dendroaspis-type natriuretic peptides (DNP) was named after its source of initial discovery – the venom of the green mamba (Dendroaspis angusticeps) in 1992 [92]. The four peptides are encoded by different genes but possess a common characteristic 17-amino-acid ring structure which contains several conserved amino acids. More recently yet another hormone – urodilatin (Uro), a structural homologue of ANP, has been included in the NP family [94].

Natriuretic Peptide Function

NPs are endogenous hormones with primary functions linked to maintenance of cardiovascular homeostasis. The main physiological actions of these peptides include: augmentation of diuresis and natriuresis rates; vasodilation; inhibition of renin, vasopressin and aldosterone secretion; suppression of cardiac sympathetic nervous system activity; inhibition of cardiac cell growth and proliferation. These properties identify them as important regulators of the blood pressure and volume systems [95].

Natriuretic Peptide Synthesis

Generally, all natriuretic peptides are synthesized as immature peptides, or preprohormones. They are then cleaved in a multi-step process to release the mature, biologically active hormones into the circulation. Upon release, the mature peptides bind to the extracellular domain of natriuretic peptide receptors (NPR) on the surface of target cells. This results either in activation of a series of signalling cascades, promoting a specific biological effect, or in NP internalization and clearance. The former action follows the binding of NP to NPR type A or B, while peptide clearance results from NP binding to NPRC. ANP, BNP, DNP, and urodilatin preferentially bind NPRA; CNP tends to bind NPR-B; and all peptide hormones can bind NPRC which ensures that a balance between NP secretion and clearance rates is maintained (reviewed in [96, 97]).

Although they belong to the same family and have a few structural similarities, common processing machinery and signalling pathways, NPs have distinct but fairly overlapping functions. ANP and BNP are synthesized predominantly by the cardiac muscle cells of the atria (ANP) and ventricles (BNP) in response to cardiac wall stretch from increased intravascular volume or pressure and diffuse into the circulation. They act locally in the heart where considerable amounts of natriuretic receptors are present, and also in various tissues in the body to relieve cardiovascular stress by promoting vasodilation, natriuresis and diuresis [98-100].

The primary source of CNP is the vascular endothelium, and the main function of the peptide was shown to be the regulation of smooth muscle excitation [101]. CNP is also abundantly expressed in the brain and nervous system and recently expression was detected in myocardial tissue with potential implications in protection of the tissue against the remodelling effects occurring post-myocardial infarction [102].

DNP was identified in mammalian plasma and although it is known to mediate vasorelaxant properties, not much is known about its origins or pathophysiological importance [103]. Urodilatin is considered to be the major NP implicated in the regulation of renal homeostasis and is predominantly synthesized and secreted by cells of the kidney [104]. Recently, evidence has shown increased excretion of urodilatin in HF patients [105].

In the setting of HTN and HF, activation of the endogenous cardiac endocrine system, in particular ANP and BNP, has been shown to play a crucial role [93, 96, 97, 106]. Although both hormones have important regulatory functions in the heart, clinically, BNP has consistently shown to have much greater diagnostic, prognostic and therapeutic benefits than ANP in relation to HF [106, 107]. Therefore, studying BNP in the context of heart disease has been the major focus of this work and the molecular and clinical characteristics/properties of the peptide are discussed in detail next.

Molecular processing of B-type natriuretic peptide

In the event of volume expansion or pressure overload, the resulting cardiac wall stretch stimulates the synthesis of human pre-proBNP in the ventricular myocardium. The 132-amino acid pre-prohormone is processed to a108 amino acid precursor protein (proBNP1-108) and then cleaved by an unknown protease into a non-active 76-amino acid N-terminal fragment, known as N-terminal pro-BNP (NTproBNP), and the biologically active, mature peptide – BNP1-32 [99].Unlike ANP, which is stored as 126-amino acid prohormone in dense granules in atrial myocytes, BNP is immediately processed to its 32-amino acid form and ventricular BNP release is directly regulated by the pathophysiological changes occurring in the diseased heart. Hence, when needed BNP is rapidly released from its cleaved BNP1-32 form. BNP gene expression in the cardiac atria and ventricles is induced within 1h from the event of cardiomyocyte stretch following increased venous volume and/or pressure [108, 109] and the plasma half-life of BNP1-32 was shown to be about 21 min [110].

Gene expression and BNP release

The tightly regulated gene expression and rapidly induced release of BNP under conditions of cardiac stress, its relatively long plasma half-life of about 21 min (compared to a half-life of 1-3 min for ANP) and its low affinity for NPRC (much lower than these of ANP and CNP) all identify BNP as probably the most promising peptide hormone from the NP family which could be successfully used for various clinical and laboratory purposes [110, 111].

Once released, BNP binds to NPRA thus triggering the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is the preferred secondary messenger for this system. Elevation of intracellular cGMP concentrations activates cGMP-dependant protein kinases (PKG), cGMP binding phosphodiesterases (PDE) and cyclic nucleotide-gated ion channels. The major NP-induced cellular effects on the vasculature and in the heart are known to result from cGMP signalling through PKG [112, 113]. PKG1 is the major cGMP-dependent protein kinase in the cardiovascular system being expressed by VSMC, platelets, and cardiomyocytes [114]. PKG1 is an important regulator of key cardiac processes including vasorelaxation (control of ion channels in VSMC to produce hyperpolarisation and vascular relaxation), vascular remodelling (regulation of VSMC growth and proliferation), platelet function (interference with platelet adhesion and aggregation), cardiac contractility and remodelling (dual involvement in contractility; inhibition of cardiomyocyte hypertrophy) [115].

References

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