Unwinding the interaction of natriuretic peptides and neprilysin.

N atriuretic peptides are an important aid for the diagnosis of heart failure (HF) and may allow for the monitoring of therapy in patients with HF over time. One view often taken to simplify their use is that elevated values reflect a more exuberant counterregulatory response to hemodynamic stress, such that these elevated levels are therefore indicative of the severity of HF and thus reflect prognosis. However, it has been clear from a variety of studies that the natriuretic peptide system is far more complex. It is highly dysfunctional in HF; in many of these patients, it is difficult to detect significant quantities of bioactive B-type natriuretic peptide (BNP) 1-32 (1). Much of the BNP measured by contemporary assays is either nonprocessed proBNP or degradation products of BNP 1-32, such as BNP 3-32, BNP 5-32, and BNP 8-32 (1). The reasons for this have recently begun to be appreciated. ProBNP, which contains 108 amino acids, needs to be cleaved into constituents (a presumably inert N-terminal proBNP [NT-proBNP] fragment and active BNP 1-32), and that requires not only convertases such as corin (a transmembrane and soluble protease) and furin (an intercellular endopeptidase) but also the lack of glycosylation (or deglycosylation) of proBNP at amino acid 71 (threonine; i.e., T71). In the case of glycosylation at T71, it appears that proBNP processing is inhibited, and for that reason, more proBNP may be generated. ProBNP is much less potent in stimulating