European Journal of Heart Failure

European Journal of Heart Failure 2004 6(3):257-260; doi:10.1016/j.ejheart.2003.12.015

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© 2004 European Society of Cardiology

Essential biochemistry and physiology of (NT-pro)BNP

Christian Hall^*

Research Institute for Internal Medicine, University of Oslo Rikshospitalet, 0037 Oslo, Norway

^* Tel.: +47-23073612; Fax: +47-23073630 E-mail address: Christian.hall{at}klinmed.uio.no

	Abstract

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
Brain natriuretic peptide (BNP) is a 32 amino acid cardiac natriuretic peptide hormone originally isolated from porcine brain tissue. The human BNP gene is located on chromosome 1 and encodes the prohormone proBNP. The biologically active BNP and the remaining part of the prohormone, NT-proBNP (76 amino acids) can be measured by immunoassay in human blood. Cardiac myocytes constitute the major source of BNP related peptides. The main stimulus for peptide synthesis and secretion is myocyte stretch. Recently, cardiac fibroblasts have also been shown to produce BNP. Other neurohormones may stimulate cardiac BNP production in different cardiac cell types. In contrast to atrial natriuretic peptides (ANP/NT-proANP), which originate mainly from atrial tissue, BNP related peptides are produced mainly from ventricular myocytes. Ventricular (NT-pro)BNP production is strongly upregulated in cardiac failure and locally in the area surrounding a myocardial infarction. In peripheral organs BNP binds to the natriuretic peptide receptor type A causing increased intracellular cGMP production. The biological effects include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. In mice BNP gene knockout leads to cardiac fibrosis, gene over-expression to hypotension and bone malformations. BNP is cleared from plasma through binding to the natriuretic peptide clearance receptor type C, but it seems relatively resistant to proteolysis by neutral endopeptidase NEP 24.11. Clearance mechanisms for NT-proBNP await further study. While the plasma concentration of NT-proBNP and BNP is approximately equal in normal controls, NT-proBNP plasma concentration is 2–10 times higher than BNP in patients with heart failure. This relative change in peptide levels may be explained by shifts in cardiac secretion and/or clearance mechanisms.

Key Words: Brain natriuretic peptide • Human • Prohormone

Received December 3, 2003; Accepted December 20, 2003

	1. Introduction

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
The suspicion that the heart may have an endocrine function was raised approximately 50 years ago. At the time it was shown that dilatation of cardiac atria produced natriuresis [1]. Furthermore, demonstration by electron microscopy of intracellular granules in atrial myocytes resembling those found in endocrine cells, supported the notion that the heart might be an endocrine organ [2]. The definitive demonstration of this was provided by deBold and associates in their classic experiment published in 1981 [3]. They injected extracts from atrial myocytes into rats and a brisk natriuresis and diuresis was observed. Flynn later showed that the active factor, termed atrial natriuretic factor (ANF), later atrial natriuretic peptide (ANP), was a 28 amino acid peptide containing a disulfide bridge constituting a ring structure [4].

In 1988 Sudoh working in Matsuo's research group demonstrated an ANP-like natriuretic peptide from porcine brain, named brain natriuretic peptide (BNP) [5]. Subsequent experiments showed that BNP was produced in cardiac myocytes and that it shared peripheral receptors with ANP [6]. Thus, today we know that the heart secretes two cardiac natriuretic peptides with a homologous structure, ANP and BNP (Fig. 1). A third homologous natriuretic peptide, termed CNP, is produced in brain and endothelium, but apparently not in cardiac myocytes.

View larger version (12K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Cardiac natriuretic peptides ANP (28 aminoacids) and BNP (32 aminoacids) are homologous in structure, forming a ring with a disulfide bridge. Identical aminoacids are marked black.

 

	2. Structure and measurement of (Nt-pro)BNP

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
The human BNP gene is located on chromosome 1 and encodes the 108 amino acid prohormone proBNP. In the circulation the biologically active 32 amino acid BNP hormone is separate from the n-terminal part of the prohormone termed NT-proBNP (Fig. 2). It is currently debated when and where the prohormone split takes place since small amounts of intact proBNP may be found in the circulation and split prohormone can be found in cellular extracts. Data from in vitro experiments indicate that the proteolytic enzyme furin is responsible for splitting the prohormone into its two subsections [7].

View larger version (12K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Schematic drawing of proBNP showing enzymatic cleavage into biologically active BNP and NT-proBNP.

 
NT-proBNP and BNP can be measured by immunoassay. The first measurement of NT-ProBNP was reported by Hunt [8] while other groups have also developed their in-house methods [9–11]. Early work utilized competitive radioimmunoassays while a commercially available method from Roche Diagnostics utilizes a two-site sandwich principle and detection by chemiluminescence.

	3. Secretion of (Nt-pro)BNP

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
Cardiac myocytes constitute the major source of BNP-related peptides in the circulation. Recently, cardiac fibroblasts have also been shown to produce BNP [12]. The quantitative contribution of this latter source to circulating plasma concentrations is not known. The main stimulus for ANP and BNP peptide synthesis and secretion is cardiac wall stress [13]. In addition in vitro experiments have indicated that other neurohormones may modulate cardiac BNP production in a paracrine and possibly endocrine fashion [14]. Since increased cardiac wall stress is a common denominator of many cardiac diseases, it follows that circulating natriuretic peptides may serve as clinical biochemical markers of these states.

There are clear differences between the two cardiac natriuretic peptide systems with regard to intracellular storage and secretion mechanisms (Table 1). ANP is stored in atrial granules and atrial stretch is accompanied by a rapid outpouring of ANP-related peptides. With respect to denovo synthesis of peptide there is a relatively slow activation of the ANP gene. In contrast (Nt-pro)BNP is secreted by a constitutive mechanism. This implies that only small amounts are stored in granules and the cells are dependent on activation of the BNP gene when increased peptide secretion is called upon. However, in comparison to ANP, the activation of the BNP gene occurs more rapidly [15]. In summary, in settings where acute changes in atrial stretch is incurred the change in the circulating peptide levels are more rapid for the ANP related than for BNP related peptides [16].

View this table: [in this window] [in a new window]   Table 1 Qualitative summary of some clinically relevant physiologic characteristics of cardiac natriuretic peptide systems ANP and BNP

 
Studies comparing the peptide production in different cardiac chambers have disclosed further important differences between the two natriuretic peptide systems (Table 1). In the normal organism the atria is the main source of both peptides. However, with chronic myocyte stretch as in chronic heart failure there is an upregulation of ventricular natriuretic peptide production [17–19]. In relative terms this upregulation seems quantitatively more important for the BNP related peptides than for the ANP related peptides. Thus, in the literature BNP is often called the ventricular hormone, but this represents an oversimplification. Nevertheless, it seems clear that when atrial tissue is taken as a reference, ventricular BNP production is higher than that of ANP, especially in heart failure. Similarly, after myocardial infarction ventricular BNP production seems to be upregulated to a greater degree than ANP production, possibly secondary to local stretch mechanisms in the area surrounding the infarcted area [20].

	4. Physiological effects of (Nt-pro)BNP

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
The physiological effects of BNP have been studied by injection of BNP into the intact organism, by exposing cells or organs to increased BNP concentrations, or by the design of mice overexpressing BNP, or with BNP gene knockout. This work has shown that BNP (like ANP) binds to the natriuretic peptide receptor type A, causing increased intracellular cyclic GMP production [6]. The biological effects thus produced include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. Mice overexpressing the BNP gene exhibit systemic hypotension and bone malformations [21]. BNP knockout mice exhibit cardiac fibrosis, but no hypertension [22]. This has led to the speculation that there may be a separate hitherto unknown receptor for BNP in cardiac fibroblasts. In addition to the natriuretic peptide receptor A, BNP also binds to natriuretic peptide receptor type C, which is thought to function as a clearance receptor.

Whether NT-proBNP has biological effects on its own is currently unknown. Likewise it is unknown whether intact prohormone can bind to the peripheral receptors.

	5. Clearance of (Nt-pro)BNP

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
Natriuretic peptides are cleared from plasma by binding to the natriuretic peptide receptors, but also through proteolysis by peptidases, the most closely studied being neutral endopeptidase (NEP) 24.11. Compared to ANP, BNP, seems relatively resistant to NEP degradation [23]. Studies in sheep have demonstrated that NT-proBNP has a longer half-life than BNP [24]. Renal excretion is currently regarded its main clearance mechanism, but this topic awaits further study. Interestingly, some data have indicated that the relative concentration between NT-proBNP and BNP may shift when healthy individuals are compared with patients with heart failure [25]. The mechanism underlying this concentration shift is unknown, but it may be related to intracardiac production changes as well as a shift in the degradation and half-life secondary to receptor regulation and/or cardiac output redistribution.

	6. Summary

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 
Cardiac myocytes produce BNP prohormone, proBNP, which is encoded from the BNP gene located on chromosome 1. ProBNP is split into NT-proBNP and BNP by the protease furin. The main regulatory mechanism for cardiac (Nt-pro)BNP production is cardiac wall stress. When chronic heart failure develops there is a relative shift in cardiac (Nt-pro)BNP production from the atria to the ventricles. After secretion, BNP binds to natriuretic peptide receptors A and C. The biological effects include diuresis, vasodilatation, inhibition of renin and aldosterone production and of cardiac and vascular myocyte growth. The biological effects of NT-proBNP are unknown. Its half-life is considerably longer than that of BNP. The cardiac wall stress-hormone production link constitutes the basis for using NT-proBNP and BNP as clinical biochemical markers of cardiac disease.

	References

Top Abstract 1. Introduction 2. Structure and measurement... 3. Secretion of (Nt-pro)BNP 4. Physiological effects of... 5. Clearance of (Nt-pro)BNP 6. Summary References

 

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