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Biochemistry of pro-B-type natriuretic peptide-derived peptides: the endocrine heart revisited.

It has been more than 40 years since the first anatomical clues to an endocrine function of the heart were reported. Electron microscopy revealed secretory granules in atrial myocytes, which structurally resembled storage granules in peptide-hormone-producing cells (1, 2). It was only in 1981, however, that Adolfo de Bold and his coworkers (3) put the endocrine heart to the test and infused extracts of atrial tissue into anesthetized rats. The infusion elicited prompt renal excretion of sodium and water, decreased the blood pressure, and increased the hematocrit. The substance was logically named atrial natriuretic factor. Soon after, this factor was purified and identified as a peptide of 28 amino acid residues (4,5) and was named atrial natriuretic peptide (ANP). [1] This discovery of a new peptide paved the way for the later identification of two different but structurally related peptides in porcine brain: brain natriuretic peptide (BNP) and C-type natriuretic peptide (6, 7). However, BNP was found to be produced mainly in the heart (8-11), and the name "brain natriuretic peptide" now is often replaced with "B-type natriuretic peptide".

The endocrine heart gained further clinical interest when it was reported that patients with congestive heart failure displayed increased plasma concentrations of ANP (12). In parallel, BNP was also shown to circulate in highly increased concentrations in heart failure patients (13,14). The concept of a plasma marker in heart failure was thereby introduced and has since been intensely pursued, with a strong focus on clinical applications. In addition, N-terminal fragments from the cardiac precursor peptides proANP and proBNP were also found to circulate in plasma and provided new molecular markers for biochemical detection of heart failure (15,16). At present, proBNP-derived peptides are the most frequently used plasma markers of congestive heart failure. The clinical aspects of proBNP-derived peptides are accordingly frequently and extensively being reviewed (17-30).

Much less is known about the structural biochemistry of the proBNP-derived peptides. For example, cardiac peptide synthesis and secretion remain poorly characterized. Current information on the molecular heterogeneity of proBNP-derived peptides in tissue and plasma suggests an overall simple cellular maturation. However, only the bioactive BNP-32 peptide has been identified, whereas the primary structure of proBNP and its N-terminal fragments remain deduced only from the cDNA sequence. Because cardiac myocytes possess a biosynthetic apparatus including several processing enzymes involved in posttranslational maturation, it seems reasonable to expect that cardiac proBNP maturation may be more complex than initially assumed. In addition, clinical results now imply that plasma concentrations of the different proBNP-derived peptides can vary greatly, which suggests that the myocytes may not always release the peptides on a simple equimolar basis. Finally, there is a peculiar paradox in increased plasma concentrations of cardiac natriuretic peptides in congestive heart failure patients suffering from sodium and water retention. A more comprehensive understanding of the biochemical structures of the molecular forms in plasma may accordingly be of both analytical and biological relevance.

This review will aim at recapitulating the biochemistry of cardiac proBNP-derived peptides. In perspective, future challenges in interpreting results from the clinical use of proBNP-derived peptides may be appreciated.

Nomenclature

A rational nomenclature is essential for the understanding of peptide structure and function. It is also clinically relevant to the physician. If the measured peptide is not readily distinguishable by its name, simple comparisons of measured concentrations from one laboratory to another may confuse and potentially lead to incorrect clinical decisions. Unfortunately, the current nomenclature for the proBNP-derived peptides is far from uniform. The widespread use of abbreviations probably gained popularity because the full peptide name is rather long. However, some suggested abbreviations do not readily identify the measured peptide(s), which clearly should be the primary information within the name. For example, the abbreviation "NT-proBNP" is now most often used for a commercial method and probably refers to measurement of [proBNP.sub.1-16] (31, 32), but the abbreviation does not provide specific information on the primary structure that is actually measured. In particular, it is not clear whether "NT-proBNP" also refers to measurement of the intact precursor. In addition, another used abbreviation, "N-BNP", refers to measurement of both intact proBNP and its N-terminal fragments (33), but this abbreviation may give the incorrect impression that it is the N[H.sub.2] terminus of BNP-32 that is being measured. Thus, a rational nomenclature needs to be structurally informative and should give the names in relation to their origin, i.e., with insight in and reference to the posttranslational processing of proBNP (Fig. 1). If this information is not available, then that must clearly be stated. In the following, a uniform nomenclature based on these premises will be used.

Structure of ProBNP

ProBNP is a single, well-defined molecule, a polypeptide that in humans has a length of 108 amino acid residues (Fig. 1). In rodents such as the rat and mouse, the primary structure is slightly shorter but has a similar C-terminal region, which contains the bioactive, receptor-binding sequence (Fig. 2). The mammalian precursor sequences have been deduced from the BNP cDNA sequence that encodes the entire preproBNP molecule (34-38). In addition to proBNP, human preproBNP contains an N-terminal hydrophobic signal peptide of 26 amino acid residues (Fig. 2), but the signal peptide is removed cotranslationally during protein synthesis in the rough endoplasmic reticulum before synthesis of the C-terminal part of the prohormone sequence is completed. It is therefore important to realize that the preproBNP molecule does not exist in real life but is only as a theoretical concept. In contrast, proBNP is likely an existing small protein, the existence of which to date has been indicated by chromatographic studies and sequence-specific immunoassays (16, 39, 40). However, the actual precursor has not been identified on a molecular level, nor have the fragments thereof, apart from the C-terminal BNP-32 peptide itself (10). Thus, it must be emphasized that whenever the primary structures of proBNP-derived peptides are mentioned in the literature, this still refers only to the cDNA-deduced sequence (Fig. 2).

Overall, the proBNP structure appears simple (Fig. 1). In humans, it is divided into two regions after a cleavage site in positions 73-76 (Arg-Ala-Pro-Arg). The first region is an N-terminal 1-76 fragment, and the second region is the C-terminal BNP-32. In contrast to many other prohormones, proBNP does not contain a third C-terminal region. Rather, the structure mostly resembles the other natriuretic peptides, in which the C-terminal region is a ring formed by a disulfide bond between the cysteinyl residues in positions 86 and 102, respectively (Fig. 2). This disulfide bridge seems essential for BNP receptor binding and biological activity (41). To date, no other proBNP-derived peptides have been identified, which leaves a molecular pattern consisting of only three peptides: intact proBNP, [proBNP.sub.1-76,] and [proBNP.sub.77-108]; the latter is reasonably named BNP-32 because of its biological effects and molecular size.

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Cellular ProBNP Storage

BNP gene expression is a feature of both atrial and ventricular myocytes. In the healthy heart, BNP gene expression occurs mainly in the atria (42, 43). However, ventricular BNP gene expression is up-regulated in diseases that affect the ventricles, such as heart failure (44). This observation may have given rise to the frequent but incorrect statement that BNP is a ventricular hormone. Atrial and ventricular myocytes differ considerably with respect to their endocrine apparatus, and it is reasonable to expect key differences in peptide storage and secretion. As mentioned, it is a well-established fact that atrial myocytes contain secretory granules for peptide storage, which led to the primary hypothesis about the endocrine heart (1, 2). Importantly, atrial granules store both intact proBNP and cleaved products, i.e., bioactive BNP-32. In contrast, ventricular myocytes in the healthy heart do not seem to produce these granules, and do not contain proBNP-derived peptides (43, 45). On the other hand, there have been some reports on both secretory granules and proBNP-derived peptides in ventricular myocytes from diseased hearts (45-47). Thus, the ventricular myocytes not only up-regulate the BNP gene but also seem to differentiate with respect to the biosynthetic apparatus. Therefore, the cellular storage and secretion of proBNP-derived peptides are complex, and the prevailing concept of regulated atrial secretion and constitutive-like ventricular release should still be a strong issue in basic research. Development of biologically relevant in vitro models would be most valuable for such studies. Finally, other cells within the heart also express the BNP gene: cardiac fibroblasts were recently shown to produce and release BNP-32 (48), Moreover, the coronary vasculature also expresses the BNP gene, at least in coronary atherosclerosis (49). Clearly, the precise proBNP storage and secretion from these cells needs to be explored.

Processing of ProBNP

Cardiac processing of proBNP is still poorly characterized. One major reason is the troublesome lack of useful in vitro cellular models (42). Although neonatal atrial myocytes can be cultured for short periods of time, they do not resemble the differentiated atrial or ventricular myocytes. Moreover, only a few sequence-specific assays have been developed for the various regions within the proBNP molecule, apart from the NHZ and COOH termini. Accordingly, the available information on posttranslational proBNP processing is partially based on indirect observations, i.e., from chromatographic studies without precise calibrators.

At first, proBNP was suggested to be cleaved by the ubiquitous endoprotease furin because the genes for both furin and BNP are expressed in cardiac myocytes of the diseased heart (50, 51). In addition, the Arg-X-X-Arg motif in positions 73-76 in proBNP has been shown to be a target for furin-mediated cleavage. In fact, processing of proBNP can be blocked in vitro by inhibition of furin (51), and furin has been shown to be critical in the processing of the structurally related peptide, pro-C-type natriuretic peptide (52). Recently, a novel protease named corin was identified from human heart cDNA (53, 54). Corin is a serine protease that can cleave both proANP and proBNP in vitro; presumably at a similar cleavage site (55, 56). Moreover, corin contains a transmembrane domain, is located within the cell membrane, and has been suggested to cleave the precursors on secretion (56). The enzymatic activity does not require the transmembrane domain, however, because a mutant soluble form is also capable of processing proANP (57). At present therefore, corin seems to be a candidate for cardiac proBNP maturation and may be involved in the generation of [proBNP.sub.1-76] and BNP-32. On the other hand, no reported study has elucidated exactly where corin cleaves the primary proBNP structure. Moreover, atrial processing of proANP and proBNP differs: isolated atrial granules have been shown to contain proANP and BNP-32 (58). Thus, corin activity does not fully explain the posttranslational processing of cardiac natriuretic peptides.

A well-established family of intracellular processing enzymes involved in prohormone maturation is the prohormone convertases (PCs). In addition to the abovementioned furin, the subtilisin-like endoproteases PC1 and PC2 are also produced in rat heart (59, 60), and PC1 production has recently been shown in healthy and diseased human cardiac tissue (61). Interestingly, atrial myocytes transfected with an adenoviral vector that expresses PC1 can process proANP to both mature ANP and to a truncated form (62). Although the precise cleavage site was not established and the processing capacity was very inefficient, this singular report does raise the possibility that other endoproteases may be involved in the posttranslational maturation of proBNP. Importantly, PC1 is active in secretory granules and could therefore be a feature of atrial proBNP processing. We are currently examining the cellular processing of proBNP by expressing the human BNP gene in endocrine cells. Preliminary results indicate that cells that produce PC1 do process proBNP, which supports the idea of PC1 as a candidate in cardiac posttranslational maturation of proBNP. Unfortunately, there is still no information on cardiac proBNP processing at other potential cleavage sites in the precursor (Fig. 1). Thus, there is a need for molecular identification of proBNP-derived peptides in cardiac tissue, which would give further insight into the cardiac processing of proBNP. Moreover, such information could be useful for designing new diagnostic immunoassays.

ProBNP-Derived Peptides in Plasma

ProBNP-derived peptides are secreted by the cardiac myocytes and circulate in plasma. Their molecular heterogeneity has been examined by chromatography and sequence-specific immunoassays. It is established that BNP-32 is secreted directly from the heart (63) and circulates without binding to plasma proteins. However, synthetic BNP-32 is trimmed when incubated in whole blood, which generates a dominant BNP form lacking the two N-terminal amino acid residues (Ser-Pro; Fig. 2) (64). Interestingly, this X-Pro motif is a known cleavage site in chemokines, cytokines, and other signal peptides (65), and enzymatic removal of the two N-terminal X-Pro residues has been demonstrated in serum (66, 67) and, recently, in intracellular vesicles (68, 69). It therefore seems likely that endogenous BNP-32 may undergo N-terminal trimming by an amino-dipeptidase. Of note, although this N-terminal region does not seem critical for receptor binding and biological activity (41), enzymatic cleavage at the NHZ terminus may be critical when choosing epitopes for antibody production and immunoassay design.

In circulation, BNP-32 is generally believed to be metabolized by a membrane-bound endopeptidase (NEP 24.11) as well as by receptor-mediated cellular uptake. The metabolic half-life of BNP-32 has been reported to be 13-20 min (70, 71). BNP-32 is also present in urine (72, 73), but the precise mechanism of renal excretion is not fully understood. We recently reported minor BNP-32 clearance by the liver, which is not significantly altered in patients with cirrhosis (74). More studies are required, however, to elucidate the precise sites of metabolism. In turn, such studies could identify disease mechanisms that may influence, and possibly even limit, the diagnostic use of plasma measurements.

In addition to BNP-32, other proBNP fragments circulate in plasma (16). These fragments are commonly referred to as "N-terminal proBNP", but the molecular heterogeneity also includes the intact precursor, in particular in heart failure patients (16, 39, 40, 75). Cardiac secretion of proBNP and its N-terminal fragments has been demonstrated by blood sampling from the coronary sinus (76, 77). The precise molar ratio of secreted [proBNP.sub.1-76] to intact proBNP has not, however, been clarified, which reflects a lack of reliable region-specific assays as well as difficulties in the chromatographic separation procedures. However, one immunoassay using antibodies raised against the COOH terminus of [proBNP.sub.1-76] has been developed (78). This assay measured [proBNP.sub.1-76] in plasma from heart failure patients, but the assay did not detect the fragment in cardiac tissue extracts. Moreover, it was suggested that intact proBNP can be processed to N-and C-terminal fragments in serum, but not in whole blood or plasma. Most proBNP, however, is processed before reaching the circulation (78). We have recently used a somewhat different strategy that bypasses some of these inherent problems (40). When we incubate plasma with trypsin before analytical measurement, the trypsin cleaves endogenous proBNP at monobasic residues to release a small [proBNP.sub.1-21] fragment (Fig. 1). In this way, both intact proBNP and [proBNP.sub.1-76] (and other possible N-terminal fragments) are processed into the same analyte, which subsequently is measured with a conventional RIA specific for the N-terminal epitope of proBNP. This processing-independent assay, designated PIA, may provide a more general approach to quantify the total amount of precursor-derived peptides in plasma (79).

Another troublesome dilemma is the unknown metabolism of proBNP and its N-terminal fragments. Apart from a single study in sheep, which suggested a longer half-life of proBNP than BNP in circulation (80), there are no pharmacokinetic data available on the elimination of proBNP. This type of information will be critical for the full interpretation of plasma measurements as well as for identification of the possible role of other organs on the circulating concentrations. Thus, the pharmacokinetics and organ clearance should be a focus for future research.

ProBNP and Oligomerization

The presence of "high-molecular-weight" proBNP in circulation has recently been suggested (81). In that report, immunoreactive N-terminal proBNP in plasma was shown to elute at a position corresponding to a much higher molecular weight than expected by chromatography, and a small synthetic proBNP-derived peptide in buffer also eluted at a position corresponding to a molecule approximately three times larger than its molecular weight. Surprisingly, the phenomenon was completely abolished in a denaturing buffer. The presence of a leucine zipper-like motif in the proBNP sequence (Fig. 2) led the authors to suggest that proBNP and its N-terminal fragments oligomerize (81). In addition, the immunoreactivity of high-molecular-weight BNP in heart failure plasma has also been reported (64, 75). We also have encountered this phenomenon, which extends even to proBNP in extracts of atrial tissue (Fig. 3). However, synthetic [proBNP.sub.1-39] with the leucine zipper-like motif substituted with alanyl residues also elutes as a molecule three times larger than the expected size, and the elution position can be reversed to the expected with use of denaturing conditions (Goetze et al., unpublished data). Thus, although proBNP and its N-terminal fragments seem to associate to something in cardiac tissue and plasma, the underlying mechanism still needs to be determined. It is nevertheless important to emphasize that such oligomerization may have a major influence on antibody detection and assay performance.

[FIGURE 3 OMITTED]

Endocrine Paradox in Heart Failure

Heart failure patients have highly increased plasma concentrations of BNP-32 (21) with marked up-regulation of BNP gene expression and subsequent high plasma concentrations of proBNP-derived peptides; it therefore seems reasonable to expect increased natriuresis. However, the opposite is the common clinical situation, with heart failure patients suffering from congestion, sodium retention, and edema. Although heart failure is a complex condition, with both activation and inhibition of nervous and hormonal systems, the paradoxical lack of ANP and BNP effects is still compelling. Of note, heart failure patients respond as expected to intravenous administration of synthetic ANP and BNP. An explanation for this endocrine paradox may be sought in the biochemistry of cardiac natriuretic peptides (82). As mentioned, both ANP and BNP are synthesized as prohormones and require posttranslational processing to release the highly potent natriuretic peptides. Importantly, the unprocessed precursors may also possess some bioactivity, which is underscored by the natriuretic effect elicited by infusion of atrial tissue homogenates containing mostly proANP. Prohormone maturation, however, seems mostly a feature of atrial peptide synthesis. In support of this, the proposed enzymes involved in proBNP maturation are produced predominantly in atrial myocytes (53, 60-62), and the ventricular myocytes do not, at least to the same extent, contain secretory granules for peptide storage and maturation. The posttranslational processing of ventricular proBNP may consequently not always be efficient in the production of potent natriuretic hormones. Immunoassays may nevertheless still detect the intact prohormone and therefore not reflect the actual bioactivity of the secreted peptides. In agreement with this suggestion, patients with congestive heart failure have increased plasma concentrations of immunoreactive N-terminal proBNP, and this immunoreactive material seems to also contain a polypeptide corresponding to the intact precursor (16, 39, 40). Thus, the congestion in heart failure patients may not be ameliorated by the secreted natriuretic peptides. Moreover, there may occasionally be large individual differences in the ability of the heart tissue to mature the precursor peptides, which could help explain why some heart failure patients suffer from severe congestion and edema, whereas other patients have much less congestion. Although this suggestion is still hypothetical, it could be worthwhile to focus more on the molar differences among proBNP-derived peptides in plasma. For example, patients with highly increased proBNP and N-terminal fragments but only modestly increased BNP-32 concentrations in plasma could be compared with patients with high BNP-32 concentrations. Finally, precursor peptides in plasma may be a future target for drug treatment because circulating precursors perhaps could be activated to mature BNP-32 and, thus, to potent hormonal activity.

[FIGURE 4 OMITTED]

Conclusions

Since the principal discovery of the cardiac hormones almost 25 years ago, a tremendous amount of research has identified the proBNP-derived peptides as useful plasma markers in heart failure (Fig. 4). It even seems likely that these peptides may become the most frequently measured peptides in the clinical routine. In contrast, our present understanding of the structural biochemistry is still far from complete. In particular, cellular synthesis, including posttranslational maturation and metabolism of the peptides, is poorly characterized. Further elucidation of the molecular heterogeneity could provide important biological insight into the endocrine heart and could likely have important diagnostic consequences. Above all, the different proBNP-derived peptides may not always be equal markers of the same pathophysiologic processes. In addition, differences in elimination may introduce new boundaries for diagnostic use. With the need for markers in heart failure being firmly documented, it now seems important to focus more on the biology of the proBNP-derived peptides. In turn, new insights into the structural biochemistry could pave the way for better and more disease-specific measurements in the clinical setting.

I am grateful to Professor Jens F. Rehfeld for his continuous encouragement and inspiration in my work with peptide hormones and their precursors.

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[1] Nonstandard abbreviations: ANP, atria] (A-type) natriuretic peptide; BNP, brain (B-type) natriuretic peptide; proANP and proBNP, propeptides of A- and B-type natriuretic peptide, respectively; and PC, prohormone convertase.

Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark. Fax 45-3545-4640; e-mail JPG@dadlnet.dk.

Received March 16, 2004; accepted June 21, 2004.

Previously published online at DOI: 10.1373/clinchem.2004.034272
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Date:Sep 1, 2004
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