Neprilysin (NEP) is currently a focus of interest in cardiovascular medicine because of the impressive benefits of combining NEP inhibition and angiotensin 2 type 1 receptor blockade, demonstrated in the PARADIGM-HF. The gene encoding human NEP is on chromosome 3 (3q21-27); it spans >80 kb and contains 24 exons. NEP is an integral type II, membrane-bound, zinc-dependent endopeptidase composed of 749 amino-acid residues. NEP is found in epithelia, fibroblasts, and neutrophils and in soluble form in the circulation, urine, and cerebrospinal fluid (CSF). In the circulation, NEP is a soluble circulating enzyme, and it is also present on the plasma membranes of neutrophils, where it may cleave the chemotactic peptide fMet-Leu-Phe and modulate the chemotactic response of neutrophils. Soluble neprilysin (sNEP) in blood, urine, and CSF retains catalytic activity, as demonstrated by assays of plasma NEP activity. NEP is expressed in cardiac fibroblasts and cardiomyocytes, and it appears to be more important than angiotensin-converting enzyme (ACE) in clearance of cardiac bradykinin. The distribution of NEP, coupled with the many established and candidate substrates of the enzyme, point to potential roles in multiple organ systems in health and disease. The NPs atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are of predominantly cardiac origin, whereas C-type natriuretic peptide (CNP) is largely sourced from endothelial cells throughout the systemic vasculature. NEP is responsible for the initial proteolytic cleavage of ANP and CNP. In humans, BNP is relatively resistant to degradation by NEP.


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