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      Brain Natriuretic Peptide and Its Biochemical, Analytical, and Clinical Issues in Heart Failure: A Narrative Review

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          Abstract

          Heart failure (HF) is a primary cause of morbidity and mortality worldwide. As the most widely studied and commonly applied natriuretic peptide (NP), B-type natriuretic peptide (BNP) has the effects of diuresis, natriuresis, vasodilation, anti-hypertrophy, and anti-fibrosis and it inhibits the renin-angiotensin-aldosterone and sympathetic nervous systems to maintain cardiorenal homeostasis and counteract the effects of HF. Both BNP and N-terminal pro B-type natriuretic peptide (NT-proBNP) are applied as diagnostic, managing, and prognostic tools for HF. However, due to the complexity of BNP system, the diversity of BNP forms and the heterogeneity of HF status, there are biochemical, analytical, and clinical issues on BNP not fully understood. Current immunoassays cross-react to varying degrees with pro B-type natriuretic peptide (proBNP), NT-proBNP and various BNP forms and cannot effectively differentiate between these forms. Moreover, current immunoassays have different results and may not accurately reflect cardiac function. It is essential to design assays that can recognize specific forms of BNP, NT-proBNP, and proBNP to obtain more clinical information. Not only the processing of proBNP (corin/furin) and BNP (neprilysin), but also the effects of glycosylation on proBNP processing and BNP assays, should be targeted in future studies to enhance their diagnostic, therapeutic, and prognostic values.

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          Most cited references72

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          ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2008: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2008 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association of the ESC (HFA) and endorsed by the European Society of Intensive Care Medicine (ESICM).

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            Recommendations for the use of natriuretic peptides in acute cardiac care: a position statement from the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care.

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              PCSK6-mediated corin activation is essential for normal blood pressure.

              Hypertension is the most common cardiovascular disease, afflicting >30% of adults. The cause of hypertension in most individuals remains unknown, suggesting that additional contributing factors have yet to be discovered. Corin is a serine protease that activates the natriuretic peptides, thereby regulating blood pressure. It is synthesized as a zymogen that is activated by proteolytic cleavage. CORIN variants and mutations impairing corin activation have been identified in people with hypertension and pre-eclampsia. To date, however, the identity of the protease that activates corin remains elusive. Here we show that proprotein convertase subtilisin/kexin-6 (PCSK6, also named PACE4; ref. 10) cleaves and activates corin. In cultured cells, we found that corin activation was inhibited by inhibitors of PCSK family proteases and by small interfering RNAs blocking PCSK6 expression. Conversely, PCSK6 overexpression enhanced corin activation. In addition, purified PCSK6 cleaved wild-type corin but not the R801A variant that lacks the conserved activation site. Pcsk6-knockout mice developed salt-sensitive hypertension, and corin activation and pro-atrial natriuretic peptide processing activity were undetectable in these mice. Moreover, we found that CORIN variants in individuals with hypertension and pre-eclampsia were defective in PCSK6-mediated activation. We also identified a PCSK6 mutation that impaired corin activation activity in a hypertensive patient. Our results indicate that PCSK6 is the long-sought corin activator and is important for sodium homeostasis and normal blood pressure.
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                Author and article information

                Contributors
                Journal
                Front Physiol
                Front Physiol
                Front. Physiol.
                Frontiers in Physiology
                Frontiers Media S.A.
                1664-042X
                05 June 2018
                2018
                : 9
                : 692
                Affiliations
                [1] 1Department of Geriatric Cardiology, Chinese People’s Liberation Army General Hospital , Beijing, China
                [2] 2Department of Cardiology and Hainan Branch, Chinese People’s Liberation Army General Hospital , Beijing, China
                [3] 3Department of Pharmaceutical Care, Chinese People’s Liberation Army General Hospital , Beijing, China
                Author notes

                Edited by: Gabriele Giacomo Schiattarella, Università degli Studi di Napoli Federico II, Italy

                Reviewed by: Matilde Otero-Losada, Instituto de Investigaciones Cardiológicas (ININCA), Argentina; Dennis W. T. Nilsen, Stavanger University Hospital, Norway; Gennaro Pagano, King’s College London, United Kingdom

                *Correspondence: Ping Ye, sci301@ 123456126.com Leiming Luo, lleim@ 123456sina.com

                These authors are joint first authors.

                This article was submitted to Clinical and Translational Physiology, a section of the journal Frontiers in Physiology

                Article
                10.3389/fphys.2018.00692
                5996066
                29922182
                160dbcd9-6f58-4f5f-90b6-7e7444725e8e
                Copyright © 2018 Fu, Ping, Zhu, Ye and Luo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 March 2018
                : 17 May 2018
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 78, Pages: 8, Words: 0
                Categories
                Physiology
                Review

                Anatomy & Physiology
                a disintegrin and metalloprotease,b-type natriuretic peptide,chronic kidney disease,corin,furin,heart failure,lcz696,proprotein convertase subtilisin/kexin-6

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