Skip to main content
SpringerLink
Log in

Neutral Endopeptidase (Neprilysin) in Therapy and Diagnostics: Yin and Yang

  • Review
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

Neprilysin (NEP) is a zinc-dependent metalloproteinase that exists in organisms in both transmembrane and soluble forms. NEP substrates are involved in regulating the cardiovascular and nervous systems. In this review, we discuss some of the biochemical characteristics and physiological functions of this enzyme with special emphasis on the use of NEP as a therapeutic target. The history and various physiological aspects of applying NEP inhibitors for treating heart failure and attempts to increase NEP activity when treating Alzheimer’s disease using gene and cell therapies are described. Another important issue discussed is the role of NEP as a potential marker for predicting the risk of cardiovascular disease complications. The diagnostic and prognostic performance of soluble NEP in various types of heart failure is analyzed and presented. We also discuss the methods and approaches for measuring NEP activity for prognosis and diagnosis, as well as a possible new role of natriuretic peptides (NEP substrates) in cardiovascular diagnostics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

Aβ:

amyloid-β peptide

ACE:

angiotensin-converting enzyme

AD:

Alzheimer’s disease

ANP:

A-type natriuretic peptide

APP:

amyloid peptide precursor

ARNi:

angiotensin receptor-neprilysin inhibitor

BNP:

B-type natriuretic peptide

CNP:

C-type natriuretic peptide

HF:

heart failure

NP:

natriuretic peptide

RAAS:

renin-angiotensin-aldosterone system

sAPP:

soluble fragment of amyloid precursor protein

(s)NEP:

(soluble) neprilysin

References

  1. McMurray, J. J., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J., Shi, V. C., Solomon, S. D., Swedberg, K., Zile, M. R., and PARADIGM-HF Committees and Investigators (2013) Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the prospective comparison of ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial (PARADIGM-HF), Eur. J. Heart Fail., 15, 1062–1073.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. George, S. G., and Kenny, J. (1973) Studies on the enzymology of purified preparations of brush border from rabbit kidney, Biochem. J., 134, 43–57.

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Malfroy, B., and Guyon, A. (1978) High-affinity degrading peptidase in brain is increased after morphine, Nature, 276, 523–526.

    Article  CAS  PubMed  Google Scholar 

  4. Roques, B. P., Fournie-Zaluski, M. C., Soroca, E., Lecomte, J. M., Malfroy, B., Llorens, C., and Schwartz, J. C. (1980) The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice, Nature, 288, 286–288.

    Article  CAS  PubMed  Google Scholar 

  5. Letarte, M., Vera, S., Tran, R., Addis, J. B., Onizuka, R. J., Quackenbush, E. J., Jongeneel, C. V., and McInnes, R. R. (1988) Common acute lymphocytic leukemia antigen is identical to neutral endopeptidase, J. Exp. Med., 168, 1247–1253.

    Article  CAS  PubMed  Google Scholar 

  6. Fulcher, I. S., and Kenny, A. J. (1983) Proteins of the kidney microvillar membrane. The amphipathic forms of endopeptidase purified from pig kidneys, Biochem. J., 211, 743–753.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Oefner, C., D’Acy, A., Hennig, M., Winkler, F. K., and Dale, G. E. (2000) Structure of human neutral endopeptidase (neprilysin) complexed with phosphoramidon, J. Mol. Biol., 296, 341–349.

    Article  CAS  PubMed  Google Scholar 

  8. Beaumont, A., Le Moual, H., Boileau, G., Crine, P., and Roques, B. P. (1991) Evidence that both arginine 102 and arginine 747 are involved in substrate binding to neutral endopeptidase (EC 3.4.24.11), J. Biol. Chem., 266, 214–220.

    CAS  PubMed  Google Scholar 

  9. Erdos, E. G., and Skidgel, R. A. (1989) Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones, FASEB J., 3, 145–151.

    Article  CAS  PubMed  Google Scholar 

  10. Ronco, P., Pollard, H., Galceran, M., Delauche, M., Schwartz, J. C., and Verroust, P. (1988) Distribution of enkephalinase (membrane metalloendopeptidase, EC 3.4.24.11) in rat organs. Detection using a monoclonal antibody, Lab. Invest., 58, 210–217.

    CAS  PubMed  Google Scholar 

  11. Mapp, P. I., Walsh, D. A., Kidd, B. L., Cruwys, S. C., Polak, J. M., and Blake, D. R. (1992) Localization of the enzyme neutral endopeptidase to the human synovium, J. Rheumatol., 19, 1838–1844.

    CAS  PubMed  Google Scholar 

  12. Bowes, M. A., and Kenny, A. J. (1986) Endopeptidase 24.11 in pig lymph nodes. Purification and immunocytochemical localization in reticular cells, Biochem. J., 236, 801–810.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Connelly, J. C., Skidgel, R. A., Schulz, W. W., Johnson, A. R., and Erdos, E. G. (1985) Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide, Proc. Natl. Acad. Sci. USA, 82, 8737–8741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuruppu, S., Rajapakse, N. W., Minond, D., and Smith, A. I. (2014) Production of soluble neprilysin by endothelial cells, Biochem. Biophys. Res. Commun., 446, 423–427.

    Article  CAS  PubMed  Google Scholar 

  15. Spillantini, M. G., Sicuteri, F., Salmon, S., and Malfroy, B. (1990) Characterization of endopeptidase 3.4.24.11 (“enkephalinase”) activity in human plasma and cerebrospinal fluid, Biochem. Pharmacol., 39, 1353–1356.

    Article  CAS  PubMed  Google Scholar 

  16. Yandle, T., Richards, M., Smith, M., Charles, C., Livesey, J., and Espiner, E. (1992) Assay of endopeptidase 24.11 activity in plasma applied to in vivo studies of endopeptidase inhibitors, Clin. Chem., 38, 1785–1791.

    CAS  PubMed  Google Scholar 

  17. Whyteside, A. R., and Turner, A. J. (2008) Human neprilysin-2 (NEP2) and NEP display distinct subcellular localisations and substrate preferences, FEBS Lett., 582, 2382–2386.

    Article  CAS  PubMed  Google Scholar 

  18. Raharjo, S. B., Emoto, N., Ikeda, K., Sato, R., Yokoyama, M., and Matsuo, M. (2001) Alternative splicing regulates the endoplasmic reticulum localization or secretion of soluble secreted endopeptidase, J. Biol. Chem., 276, 25612–25620.

    Article  CAS  PubMed  Google Scholar 

  19. Pankow, K., Schwiebs, A., Becker, M., Siems, W. E., Krause, G., and Walther, T. (2009) Structural substrate conditions required for neutral endopeptidase-mediated natriuretic peptide degradation, J. Mol. Biol., 393, 496–503.

    Article  CAS  PubMed  Google Scholar 

  20. Shipp, M. A., Tarr, G. E., Chen, C. Y., Switzer, S. N., Hersh, L. B., Stein, H., Sunday, M. E., and Reinherz, E. L. (1991) CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung, Proc. Natl. Acad. Sci. USA, 88, 10662–10666.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kenny, A. J., Bourne, A., and Ingram, J. (1993) Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C-type natriuretic peptide and some C-receptor ligands by endopeptidase 24.11, Biochem. J., 291, 83–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Watanabe, Y., Nakajima, K., Shimamori, Y., and Fujimoto, Y. (1997) Comparison of the hydrolysis of the three types of natriuretic peptides by human kidney neutral endopeptidase 24.11, Biochem. Mol. Med., 61, 47–51.

    Article  CAS  PubMed  Google Scholar 

  23. Bhoola, K. D., Figueroa, C. D., and Worthy, K. (1992) Bioregulation of kinins: kallikreins, kininogens, and kininases, Pharmacol. Rev., 44, 1–80.

    CAS  PubMed  Google Scholar 

  24. Matsas, R., Rattray, M., Kenny, A. J., and Turner, A. J. (1985) The metabolism of neuropeptides. Endopeptidase-24.11 in human synaptic membrane preparations hydrolyses substance P, Biochem. J., 228, 487–492.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wilkinson, I. B., McEniery, C. M., Bongaerts, K. H., MacCallum, H., Webb, D. J., and Cockcroft, J. R. (2001) Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP), Br. J. Clin. Pharmacol., 52, 159–164.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. McDowell, G., Coutie, W., Shaw, C., Buchanan, K. D., Struthers, A. D., and Nicholls, D. P. (1997) The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides, Br. J. Clin. Pharmacol., 43, 329–332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Barnes, K., Doherty, S., and Turner, A. J. (1995) Endopeptidase-24.11 is the integral membrane peptidase initiating degradation of somatostatin in the hippocampus, J. Neurochem., 64, 1826–1832.

    Article  CAS  PubMed  Google Scholar 

  28. Nalivaeva, N. N., Belyaev, N. D., Zhuravin, I. A., and Turner, A. J. (2012) The Alzheimer’s amyloid-degrading peptidase, neprilysin: can we control it? Int. J. Alzheimers Dis., 2012, 383796.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Singh, J. S. S., Burrell, L. M., Cherif, M., Squire, I. B., Clark, A. L., and Lang, C. C. (2017) Sacubitril/valsartan: beyond natriuretic peptides, Heart, 103, 1569–1577.

    Article  CAS  PubMed  Google Scholar 

  30. Schulz, R., Sakane, Y., Berry, C., and Ghai, R. (1991) Characterisation of neutral endopeptidase 3.4.24.11 (NEP) in the kidney: comparison between normotensive, genetically hypertensive and experimentally hypertensive rats, J. Enzyme Inhib., 4, 347–358.

    Article  CAS  PubMed  Google Scholar 

  31. Koehn, J. A., Norman, J. A., Jones, B. N., LeSueur, L., Sakane, Y., and Ghai, R. D. (1987) Degradation of atrial natriuretic factor by kidney cortex membranes. Isolation and characterization of the primary proteolytic product, J. Biol. Chem., 262, 11623–11627.

    CAS  PubMed  Google Scholar 

  32. Olins, G. M., Spear, K. L., Siegel, N. R., and Zurcher-Neely, H. A. (1987) Inactivation of atrial natriuretic factor by the renal brush border, Biochim. Biophys. Acta, 901, 97–100.

    Article  CAS  PubMed  Google Scholar 

  33. Nawarskas, J., Rajan, V., and Frishman, W. H. (2001) Vasopeptidase inhibitors, neutral endopeptidase inhibitors, and dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase, Heart Dis., 3, 378–385.

    Article  CAS  PubMed  Google Scholar 

  34. Nishimura, K., and Hazato, T. (1993) Isolation and identification of an endogenous inhibitor of enkephalin-degrading enzymes from bovine spinal cord, Biochem. Biophys. Res. Commun., 194, 713–719.

    Article  CAS  PubMed  Google Scholar 

  35. Shen, R., Sumitomo, M., Dai, J., Harris, A., Kaminetzky, D., Gao, M., Burnstein, K. L., and Nanus, D. M. (2000) Androgen-induced growth inhibition of androgen receptor expressing androgen-independent prostate cancer cells is mediated by increased levels of neutral endopeptidase, Endocrinology, 141, 1699–1704.

    Article  CAS  PubMed  Google Scholar 

  36. Stephen, H. M., Khoury, R. J., Majmudar, P. R., Blaylock, T., Hawkins, K., Salama, M. S., Scott, M. D., Cosminsky, B., Utreja, N. K., Britt, J., and Conway, R. E. (2016) Epigenetic suppression of neprilysin regulates breast cancer invasion, Oncogenesis, 5, e207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Jhund, P. S., and McMurray, J. J. (2016) The neprilysin pathway in heart failure: a review and guide on the use of sacubitril/valsartan, Heart, 102, 1342–1347.

    Article  CAS  PubMed  Google Scholar 

  38. Volpe, M., Carnovali, M., and Mastromarino, V. (2016) The natriuretic peptides system in the pathophysiology of heart failure: from molecular basis to treatment, Clin. Sci. (Lond.), 130, 57–77.

    Article  CAS  Google Scholar 

  39. Potter, L. R., Yoder, A. R., Flora, D. R., Antos, L. K., and Dickey, D. M. (2009) Natriuretic peptides: their structures, receptors, physiologic functions and therapeutic applications, Handb. Exp. Pharmacol., 191, 341–366.

    Article  CAS  Google Scholar 

  40. Yamamoto, K., Chappell, M. C., Brosnihan, K. B., and Ferrario, C. M. (1992) In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats, Hypertension, 19, 692–696.

    Article  CAS  PubMed  Google Scholar 

  41. Rossi, F., Mascolo, A., and Mollace, V. (2017) The pathophysiological role of natriuretic peptide-RAAS cross talk in heart failure, Int. J. Cardiol., 226, 121–125.

    Article  PubMed  Google Scholar 

  42. D’Elia, E., Iacovoni, A., Vaduganathan, M., Lorini, F. L., Perlini, S., and Senni, M. (2017) Neprilysin inhibition in heart failure: mechanisms and substrates beyond modulating natriuretic peptides, Eur. J. Heart Fail., 19, 710–717.

    Article  PubMed  CAS  Google Scholar 

  43. Sonnenberg, J. L., Sakane, Y., Jeng, A. Y., Koehn, J. A., Ansell, J. A., Wennogle, L. P., and Ghai, R. D. (1988) Identification of protease 3.4.24.11 as the major atrial natriuretic factor degrading enzyme in the rat kidney, Peptides, 9, 173–180.

    Article  CAS  PubMed  Google Scholar 

  44. Vanneste, Y., Michel, A., Dimaline, R., Najdovski, T., and Deschodt-Lanckman, M. (1988) Hydrolysis of alpha-human atrial natriuretic peptide in vitro by human kidney membranes and purified endopeptidase-24.11. Evidence for a novel cleavage site, Biochem. J., 254, 531–537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Ralat, L. A., Guo, Q., Ren, M., Funke, T., Dickey, D. M., Potter, L. R., and Tang, W. J. (2011) Insulin-degrading enzyme modulates the natriuretic peptide-mediated signaling response, J. Biol. Chem., 286, 4670–4679.

    Article  CAS  PubMed  Google Scholar 

  46. Muller, D., Schulze, C., Baumeister, H., Buck, F., and Richter, D. (1992) Rat insulin-degrading enzyme: cleavage pattern of the natriuretic peptide hormones ANP, BNP, and CNP revealed by HPLC and mass spectrometry, Biochemistry, 31, 11138–11143.

    Article  CAS  PubMed  Google Scholar 

  47. Dickey, D. M., and Potter, L. R. (2010) Human B-type natriuretic peptide is not degraded by meprin A, Biochem. Pharmacol., 80, 1007–1011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Norman, J. A., Little, D., Bolgar, M., and Di Donato, G. (1991) Degradation of brain natriuretic peptide by neutral endopeptidase: species specific sites of proteolysis determined by mass spectrometry, Biochem. Biophys. Res. Commun., 175, 22–30.

    Article  CAS  PubMed  Google Scholar 

  49. Semenov, A. G., and Katrukha, A. G. (2016) Different susceptibility of B-type natriuretic peptide (BNP) and BNP precursor (proBNP) to cleavage by neprilysin: the N-terminal part does matter, Clin. Chem., 62, 617–622.

    Article  CAS  PubMed  Google Scholar 

  50. Semenov, A. G., Feygina, E. E., Tamm, N. N., Serebryanaya, D. V., and Katrukha, A. G. (2017) Abstract 15828: pro-atrial natriuretic peptide (proANP) as a stable circulating ANP form that is not affected by neprilysin-mediated cleavage, Circulation, 136, A15828.

    Google Scholar 

  51. Yan, W., Wu, F., Morser, J., and Wu, Q. (2000) Corin, a transmembrane cardiac serine protease, acts as a pro-atrial natriuretic peptide-converting enzyme, Proc. Natl. Acad. Sci. USA, 97, 8525–8529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Yan, W., Sheng, N., Seto, M., Morser, J., and Wu, Q. (1999) Corin, a mosaic transmembrane serine protease encoded by a novel cDNA from human heart, J. Biol. Chem., 274, 14926–14935.

    Article  CAS  PubMed  Google Scholar 

  53. Semenov, A. G., Tamm, N. N., Seferian, K. R., Postnikov, A. B., Karpova, N. S., Serebryanaya, D. V., Koshkina, E. V., Krasnoselsky, M. I., and Katrukha, A. G. (2010) Processing of pro-B-type natriuretic peptide: furin and corin as candidate convertases, Clin. Chem., 56, 1166–1176.

    Article  PubMed  Google Scholar 

  54. Semenov, A. G., Seferian, K. R., Tamm, N. N., Artem’eva, M. M., Postnikov, A. B., Bereznikova, A. V., Kara, A. N., Medvedeva, N. A., and Katrukha, A. G. (2011) Human pro-B-type natriuretic peptide is processed in the circulation in a rat model, Clin. Chem., 57, 883–890.

    Article  CAS  PubMed  Google Scholar 

  55. Yandle, T. G., Richards, A. M., Gilbert, A., Fisher, S., Holmes, S., and Espiner, E. A. (1993) Assay of brain natriuretic peptide (BNP) in human plasma: evidence for high molecular weight BNP as a major plasma component in heart failure, J. Clin. Endocrinol. Metab., 76, 832–838.

    CAS  PubMed  Google Scholar 

  56. Seferian, K. R., Tamm, N. N., Semenov, A. G., Mukharyamova, K. S., Tolstaya, A. A., Koshkina, E. V., Kara, A. N., Krasnoselsky, M. I., Apple, F. S., Esakova, T. V., Filatov, V. L., and Katrukha, A. G. (2007) The brain natriuretic peptide (BNP) precursor is the major immunoreactive form of BNP in patients with heart failure, Clin. Chem., 53, 866–873.

    Article  CAS  PubMed  Google Scholar 

  57. Semenov, A. G., and Feygina, E. E. (2018) Standardization of BNP and NT-proBNP immunoassays in light of the diverse and complex nature of circulating BNP-related peptides, Adv. Clin. Chem., 85, 1–30.

    Article  CAS  PubMed  Google Scholar 

  58. Yandrapalli, S., Aronow, W. S., Mondal, P., and Chabbott, D. R. (2017) The evolution of natriuretic peptide augmentation in management of heart failure and the role of sacubitril/valsartan, Arch. Med. Sci., 13, 1207–1216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Northridge, D. B., Jardine, A. G., Alabaster, C. T., Barclay, P. L., Connell, J. M., Dargie, H. J., Dilly, S. G., Findlay, I. N., Lever, A. F., and Samuels, G. M. (1989) Effects of UK 69 578: a novel atriopeptidase inhibitor, Lancet, 2, 591–593.

    Article  CAS  PubMed  Google Scholar 

  60. Gros, C., Souque, A., Schwartz, J. C., Duchier, J., Cournot, A., Baumer, P., and Lecomte, J. M. (1989) Protection of atrial natriuretic factor against degradation: diuretic and natriuretic responses after in vivo inhibition of enkephalinase (EC 3.4.24.11) by acetorphan, Proc. Natl. Acad. Sci. USA, 86, 7580–7584.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Bevan, E. G., Connell, J. M., Doyle, J., Carmichael, H. A., Davies, D. L., Lorimer, A. R., and McInnes, G. T. (1992) Candoxatril, a neutral endopeptidase inhibitor: efficacy and tolerability in essential hypertension, J. Hypertens., 10, 607–613.

    Article  CAS  PubMed  Google Scholar 

  62. Richards, A. M., Wittert, G. A., Espiner, E. A., Yandle, T. G., Ikram, H., and Frampton, C. (1992) Effect of inhibition of endopeptidase 24.11 on responses to angiotensin II in human volunteers, Circ. Res., 71, 1501–1507.

    Article  CAS  PubMed  Google Scholar 

  63. Ferro, C. J., Spratt, J. C., Haynes, W. G., and Webb, D. J. (1998) Inhibition of neutral endopeptidase causes vasoconstriction of human resistance vessels in vivo, Circulation, 97, 2323–2330.

    Article  CAS  PubMed  Google Scholar 

  64. Group, C. T S. (1987) Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), N. Engl. J. Med., 316, 1429–1435.

    Article  Google Scholar 

  65. Investigators, S., Yusuf, S., Pitt, B., Davis, C. E., Hood, W. B., and Cohn, J. N. (1991) Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure, N. Engl. J. Med., 325, 293–302.

    Article  Google Scholar 

  66. Trippodo, N. C., Robl, J. A., Asaad, M. M., Bird, J. E., Panchal, B. C., Schaeffer, T. R., Fox, M., Giancarli, M. R., and Cheung, H. S. (1995) Cardiovascular effects of the novel dual inhibitor of neutral endopeptidase and angiotensin-converting enzyme BMS-182657 in experimental hypertension and heart failure, J. Pharmacol. Exp. Ther., 275, 745–752.

    CAS  PubMed  Google Scholar 

  67. McClean, D. R., Ikram, H., Garlick, A. H., Richards, A. M., Nicholls, M. G., and Crozier, I. G. (2000) The clinical, cardiac, renal, arterial and neurohormonal effects of omapatrilat, a vasopeptidase inhibitor, in patients with chronic heart failure, J. Am. Coll. Cardiol., 36, 479–486.

    Article  CAS  PubMed  Google Scholar 

  68. Rouleau, J. L., Pfeffer, M. A., Stewart, D. J., Isaac, D., Sestier, F., Kerut, E. K., Porter, C. B., Proulx, G., Qian, C., and Block, A. J. (2000) Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial, Lancet, 356, 615–620.

    Article  CAS  PubMed  Google Scholar 

  69. Packer, M., Califf, R. M., Konstam, M. A., Krum, H., McMurray, J. J., Rouleau, J. L., and Swedberg, K. (2002) Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE), Circulation, 106, 920–926.

    Article  CAS  PubMed  Google Scholar 

  70. Kostis, J. B., Packer, M., Black, H. R., Schmieder, R., Henry, D., and Levy, E. (2004) Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial, Am. J. Hypertens., 17, 103–111.

    Article  CAS  PubMed  Google Scholar 

  71. Fryer, R. M., Segreti, J., Banfor, P. N., Widomski, D. L., Backes, B. J., Lin, C. W., Ballaron, S. J., Cox, B. F., Trevillyan, J. M., Reinhart, G. A., and von Geldern, T. W. (2008) Effect of bradykinin metabolism inhibitors on evoked hypotension in rats: rank efficacy of enzymes associated with bradykinin-mediated angioedema, Br. J. Pharmacol., 153, 947–955.

    Article  CAS  PubMed  Google Scholar 

  72. McMurray, J. J., Packer, M., Desai, A. S., Gong, J., Lefkowitz, M. P., Rizkala, A. R., Rouleau, J. L., Shi, V. C., Solomon, S. D., Swedberg, K., Zile, M. R., Investigators, P. H., and Committees, (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure, N. Engl. J. Med., 371, 993–1004.

    Article  PubMed  CAS  Google Scholar 

  73. Velazquez, E. J., Morrow, D. A., DeVore, A. D., Duffy, C. I., Ambrosy, A. P., McCague, K., Rocha, R., Braunwald, E., and Investigators, P. H. (2019) Angiotensin-neprilysin inhibition in acute decompensated heart failure, N. Engl. J. Med., 380, 539–548.

    Article  CAS  PubMed  Google Scholar 

  74. Solomon, S. D., Rizkala, A. R., Gong, J., Wang, W., Anand, I. S., Ge, J., Lam, C. S. P., Maggioni, A. P., Martinez, F., Packer, M., Pfeffer, M. A., Pieske, B., Redfield, M. M., Rouleau, J. L., Van Veldhuisen, D. J., Zannad, F., Zile, M. R., Desai, A. S., Shi, V. C., Lefkowitz, M. P., and McMurray, J. J. V. (2017) Angiotensin receptor neprilysin inhibition in heart failure with preserved ejection fraction: rationale and design of the PARAGON-HF trial, JACC Heart Fail., 5, 471–482.

    Article  PubMed  Google Scholar 

  75. Solomon, S. D., Rizkala, A. R., Lefkowitz, M. P., Shi, V. C., Gong, J., et al. (2018) Baseline characteristics of patients with heart failure and preserved ejection fraction in the PARAGON-HF trial, Circ. Heart Fail., 11, e004962.

    Article  PubMed  Google Scholar 

  76. Howell, S., Nalbantoglu, J., and Crine, P. (1995) Neutral endopeptidase can hydrolyze beta-amyloid(1–40) but shows no effect on beta-amyloid precursor protein metabolism, Peptides, 16, 647–652.

    Article  CAS  PubMed  Google Scholar 

  77. Iwata, N., Tsubuki, S., Takaki, Y., Watanabe, K., Sekiguchi, M., Hosoki, E., Kawashima-Morishima, M., Lee, H. J., Hama, E., Sekine-Aizawa, Y., and Saido, T. C. (2000) Identification of the major Abeta1-42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition, Nat. Med., 6, 143–150.

    Article  CAS  PubMed  Google Scholar 

  78. Takaki, Y., Iwata, N., Tsubuki, S., Taniguchi, S., Toyoshima, S., Lu, B., Gerard, N. P., Gerard, C., Lee, H. J., Shirotani, K., and Saido, T. C. (2000) Biochemical identification of the neutral endopeptidase family member responsible for the catabolism of amyloid beta peptide in the brain, J. Biochem., 128, 897–902.

    Article  CAS  PubMed  Google Scholar 

  79. Selkoe, D. J., and Hardy, J. (2016) The amyloid hypothesis of Alzheimer’s disease at 25 years, EMBO Mol. Med., 8, 595–608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Hardy, J. A., and Higgins, G. A. (1992) Alzheimer’s disease: the amyloid cascade hypothesis, Science, 256, 184–185.

    Article  CAS  PubMed  Google Scholar 

  81. Hernandez-Zimbron, L. F., and Rivas-Arancibia, S. (2014) Deciphering an interplay of proteins associated with amyloid beta 1–42 peptide and molecular mechanisms of Alzheimer’s disease, Rev. Neurosci., 25, 773–783.

    Article  CAS  PubMed  Google Scholar 

  82. Lambert, M. P., Barlow, A. K., Chromy, B. A., Edwards, C., Freed, R., Liosatos, M., Morgan, T. E., Rozovsky, I., Trommer, B., Viola, K. L., Wals, P., Zhang, C., Finch, C. E., Krafft, G. A., and Klein, W. L. (1998) Diffusible, non-fibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins, Proc. Natl. Acad. Sci. USA, 95, 6448–6453.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Yoon, S. S., and Jo, S. A. (2012) Mechanisms of amyloid-beta peptide clearance: potential therapeutic targets for Alzheimer’s disease, Biomol. Ther. (Seoul), 20, 245–255.

    Article  CAS  Google Scholar 

  84. Bateman, R. J., Munsell, L. Y., Morris, J. C., Swarm, R., Yarasheski, K. E., and Holtzman, D. M. (2006) Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo, Nat. Med., 12, 856–861.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Mawuenyega, K. G., Sigurdson, W., Ovod, V., Munsell, L., Kasten, T., Morris, J. C., Yarasheski, K. E., and Bateman, R. J. (2010) Decreased clearance of CNS beta-amyloid in Alzheimer’s disease, Science, 330, 1774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Grimm, M. O., Mett, J., Stahlmann, C. P., Haupenthal, V. J., Zimmer, V. C., and Hartmann, T. (2013) Neprilysin and Abeta clearance: impact of the APP intracellular domain in NEP regulation and implications in Alzheimer’s disease, Front. Aging Neurosci., 5, 98.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Eckman, E. A., Adams, S. K., Troendle, F. J., Stodola, B. A., Kahn, M. A., Fauq, A. H., Xiao, H. D., Bernstein, K. E., and Eckman, C. B. (2006) Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme, J. Biol. Chem., 281, 30471–30478.

    Article  CAS  PubMed  Google Scholar 

  88. Madani, R., Poirier, R., Wolfer, D. P., Welzl, H., Groscurth, P., Lipp, H. P., Lu, B., El Mouedden, M., Mercken, M., Nitsch, R. M., and Mohajeri, M. H. (2006) Lack of neprilysin suffices to generate murine amyloid-like deposits in the brain and behavioral deficit in vivo, J. Neurosci. Res., 84, 1871–1878.

    Article  CAS  PubMed  Google Scholar 

  89. Caccamo, A., Oddo, S., Sugarman, M. C., Akbari, Y., and LaFerla, F. M. (2005) Age- and region-dependent alterations in Abeta-degrading enzymes: implications for Abeta-induced disorders, Neurobiol. Aging, 26, 645–654.

    Article  CAS  PubMed  Google Scholar 

  90. Iwata, N., Mizukami, H., Shirotani, K., Takaki, Y., Muramatsu, S., Lu, B., Gerard, N. P., Gerard, C., Ozawa, K., and Saido, T. C. (2004) Presynaptic localization of neprilysin contributes to efficient clearance of amyloid-beta peptide in mouse brain, J. Neurosci., 24, 991–998.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Marr, R. A., Rockenstein, E., Mukherjee, A., Kindy, M. S., Hersh, L. B., Gage, F. H., Verma, I. M., and Masliah, E. (2003) Neprilysin gene transfer reduces human amyloid pathology in transgenic mice, J. Neurosci., 23, 1992–1996.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Hong, C. S., Goins, W. F., Goss, J. R., Burton, E. A., and Glorioso, J. C. (2006) Herpes simplex virus RNAi and neprilysin gene transfer vectors reduce accumulation of Alzheimer’s disease-related amyloid-beta peptide in vivo, Gene Ther., 13, 1068–1079.

    Article  CAS  PubMed  Google Scholar 

  93. Hemming, M. L., Patterson, M., Reske-Nielsen, C., Lin, L., Isacson, O., and Selkoe, D. J. (2007) Reducing amyloid plaque burden via ex vivo gene delivery of an Abeta-degrading protease: a novel therapeutic approach to Alzheimer disease, PLoS Med., 4, e262.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Lin, C. Y., Perche, F., Ikegami, M., Uchida, S., Kataoka, K., and Itaka, K. (2016) Messenger RNA-based therapeutics for brain diseases: an animal study for augmenting clearance of beta-amyloid by intracerebral administration of neprilysin mRNA loaded in polyplex nanomicelles, J. Control. Release, 235, 268–275.

    Article  CAS  PubMed  Google Scholar 

  95. Nalivaeva, N. N., and Turner, A. J. (2019) Targeting amyloid clearance in Alzheimer’s disease as a therapeutic strategy, Br. J. Pharmacol., 176, 3447–3463, doi: https://doi.org/10.1111/bph.14593.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Park, M. H., Lee, J. K., Choi, S., Ahn, J., Jin, H. K., Park, J. S., and Bae, J. S. (2013) Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer’s disease mice, Brain Res., 1529, 113–124.

    Article  CAS  PubMed  Google Scholar 

  97. Vodovar, N., Paquet, C., Mebazaa, A., Launay, J. M., Hugon, J., and Cohen-Solal, A. (2015) Neprilysin, cardiovascular, and Alzheimer’s diseases: the therapeutic split? Eur. Heart J., 36, 902–905.

    Article  CAS  PubMed  Google Scholar 

  98. Langenickel, T. H., Tsubouchi, C., Ayalasomayajula, S., Pal, P., Valentin, M. A., Hinder, M., Jhee, S., Gevorkyan, H., and Rajman, I. (2016) The effect of LCZ696 (sacubitril/valsartan) on amyloid-beta concentrations in cerebrospinal fluid in healthy subjects, Br. J. Clin. Pharmacol., 81, 878–890.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Cannon, J. A., Shen, L., Jhund, P. S., Kristensen, S. L., Kober, L., Chen, F., Gong, J., Lefkowitz, M. P., Rouleau, J. L., Shi, V. C., Swedberg, K., Zile, M. R., Solomon, S. D., Packer, M., McMurray, J. J., and PARADIGM-HF Investigators and Committees (2017) Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction, Eur. J. Heart Fail., 19, 129–137.

    Article  CAS  PubMed  Google Scholar 

  100. Karnik, A. A., Gopal, D. M., Ko, D., Benjamin, E. J., and Helm, R. H. (2019) Epidemiology of atrial fibrillation and heart failure: a growing and important problem, Cardiol. Clin., 37, 119–129.

    Article  PubMed  Google Scholar 

  101. Savarese, G., and Lund, L. H. (2017) Global public health burden of heart failure, Card. Fail. Rev., 3, 7–11.

    Article  PubMed  PubMed Central  Google Scholar 

  102. Seronde, M. F., and Mebazaa, A. (2015) Neprilysin: biotarget and biomarker in heart failure, JACC Heart Fail., 3, 645–646.

    Article  PubMed  Google Scholar 

  103. Bayes-Genis, A., Barallat, J., Galan, A., de Antonio, M., Domingo, M., Zamora, E., Urrutia, A., and Lupon, J. (2015) Soluble neprilysin is predictive of cardiovascular death and heart failure hospitalization in heart failure patients, J. Am. Coll. Cardiol., 65, 657–665.

    Article  CAS  PubMed  Google Scholar 

  104. Bayes-Genis, A., Barallat, J., Galan, A., de Antonio, M., Domingo, M., Zamora, E., Gastelurrutia, P., Vila, J., Penafiel, J., Galvez-Monton, C., and Lupon, J. (2015) Multimarker strategy for heart failure prognostication. Value of neurohormonal biomarkers: neprilysin vs NT-proBNP, Rev. Esp. Cardiol. (Engl. Ed.), 68, 1075–1084.

    Article  Google Scholar 

  105. Goliasch, G., Pavo, N., Zotter-Tufaro, C., Kammerlander, A., Duca, F., Mascherbauer, J., and Bonderman, D. (2016) Soluble neprilysin does not correlate with outcome in heart failure with preserved ejection fraction, Eur. J. Heart Fail., 18, 89–93.

    Article  CAS  PubMed  Google Scholar 

  106. Bayes-Genis, A., Barallat, J., Pascual-Figal, D., Nunez, J., Minana, G., Sanchez-Mas, J., Galan, A., Sanchis, J., Zamora, E., Perez-Martinez, M. T., and Lupon, J. (2015) Prognostic value and kinetics of soluble neprilysin in acute heart failure: a pilot study, JACC Heart Fail., 3, 641–644.

    Article  PubMed  Google Scholar 

  107. Bayes-Genis, A., Barallat, J., and Richards, A. M. (2016) A test in context: neprilysin: function, inhibition, and biomarker, J. Am. Coll. Cardiol., 68, 639–653.

    Article  CAS  PubMed  Google Scholar 

  108. Vodovar, N., Seronde, M. F., Laribi, S., Gayat, E., Lassus, J., Januzzi, J. L., Jr., Boukef, R., Nouira, S., Manivet, P., Samuel, J. L., Logeart, D., Cohen-Solal, A., Richards, A. M., Launay, J. M., Mebazaa, A., and Network, G. (2015) Elevated plasma B-type natriuretic peptide concentrations directly inhibit circulating neprilysin activity in heart failure, JACC Heart Fail., 3, 629–636.

    Article  PubMed  Google Scholar 

  109. Emrich, I. E., Vodovar, N., Feuer, L., Untersteller, K., Nougue, H., Seiler-Mussler, S., Fliser, D., Launay, J. M., and Heine, G. H. (2019) Do plasma neprilysin activity and plasma neprilysin concentration predict cardiac events in chronic kidney disease patients? Nephrol. Dial. Transplant., 34, 100–108.

    Article  PubMed  Google Scholar 

  110. Zhuravin, I. A., Nalivaeva, N. N., Kozlova, D. I., Kochkina, E. G., Fedorova, Ya. B., and Gavrilova, S. I. (2015) Serum cholinesterase and neprilysin activity as potential biomarkers of mild cognitive impairment and Alzheimer’s disease, Zh. Nevrol. Psikhiatr. S. S. Korsakova, 115, 110–117, doi: https://doi.org/10.17116/jnevro2015115112110-117.

    Article  Google Scholar 

  111. Medeiros, M. A., Franca, M. S., Boileau, G., Juliano, L., and Carvalho, K. M. (1997) Specific fluorogenic substrates for neprilysin (neutral endopeptidase, EC 3.4.24.11) which are highly resistant to serine- and metalloproteases, Braz. J. Med. Biol. Res., 30, 1157–1162.

    Article  CAS  PubMed  Google Scholar 

  112. Takahashi, G., Tabata, M., Taguchi, K., and Chikuma, T. (2015) Fluorimetric assay for measuring neprilysin activity using HPLC, Chromatographia, 78, 593–597.

    Article  CAS  Google Scholar 

  113. Feygina, E. E., Artemieva, M., Postnikov, A. B., Tamm, N. N., Bloshchitsyna, M. N., Medvedeva, N. A., Katrukha, A. G., and Semenov, A. G. (2019) Detection of neprilysin-derived BNP fragments in the circulation: possible insights for targeted neprilysin inhibition therapy for heart failure, Clin. Chem., doi: https://doi.org/10.1373/clinchem.2019.303438.

    Article  PubMed  Google Scholar 

  114. Burrell, M., Henderson, S. J., Ravnefjord, A., Schweikart, F., Fowler, S. B., Witt, S., Hansson, K. M., and Webster, C. I. (2016) Neprilysin inhibits coagulation through proteolytic inactivation of fibrinogen, PLoS One, 11, e0158114.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. HyTest Ltd., 20520, Turku, Finland

    E. E. Feygina, A. G. Katrukha & A. G. Semenov

  2. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    E. E. Feygina & A. G. Semenov

  3. Faculty of Biology, Lomonosov Moscow State University, 119991, Moscow, Russia

    A. G. Katrukha

Authors
  1. E. E. Feygina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. G. Katrukha
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. G. Semenov
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to E. E. Feygina.

Additional information

Conflict of interest

The authors declare no conflict of interest.

Compliance with ethical standards

No description of studies with human subjects or animals is provided in the paper.

Russian Text © The Author(s), 2019, published in Biokhimiya, 2019, Vol. 84, No. 11, pp. 1668–1682.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Feygina, E.E., Katrukha, A.G. & Semenov, A.G. Neutral Endopeptidase (Neprilysin) in Therapy and Diagnostics: Yin and Yang. Biochemistry Moscow 84, 1346–1358 (2019). https://doi.org/10.1134/S0006297919110105

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297919110105

Keywords

Search

Navigation