Nicolas Vodovar1, Marie-France Séronde2, Said Laribi3, Etienne Gayat4, Johan Lassus5, Riadh Boukef6, Semir Nouira6, Philippe Manivet7, Jane-Lise Samuel8, Damien Logeart9, Shiro Ishihara10, Alain Cohen Solal9, James L Januzzi11, A Mark Richards12, Jean-Marie Launay13, Alexandre Mebazaa14. 1. UMRS 942 Inserm, Paris 75010, France DHU FIRE. 2. UMRS 942 Inserm, Paris 75010, France Department of Cardiology, EA3920, University Hospital Jean Minjoz, Besançon, France. 3. UMRS 942 Inserm, Paris 75010, France Department of Emergency Medicine, Lariboisière Hospital, Paris, France DHU Neurovasc. 4. UMRS 942 Inserm, Paris 75010, France DHU Neurovasc Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France. 5. Heart and Lung Center, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland. 6. Emergency Department and Research Unit UR06SP21, Fattouma Bourguiba University Hospital, Monastir, Tunisia. 7. UMRS 942 Inserm, Paris 75010, France Department of Biochemistry, Lariboisière Hospital, 2, Rue A. Paré, 75475, Paris, Cedex 10, France Center for Biological Resources, Lariboisière Hospital, Paris, France. 8. UMRS 942 Inserm, Paris 75010, France Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France. 9. UMRS 942 Inserm, Paris 75010, France DHU FIRE Department of Cardiology, Lariboisière Hospital, Paris, France Paris Diderot University, Sorbonne Paris Cité, Paris 75205, France. 10. UMRS 942 Inserm, Paris 75010, France Cardiology and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan. 11. Cardiology Division, Massachusetts General Hospital, Boston, MA, USA. 12. University of Otago, Christchurch, New Zealand National University Health System, Singarpore, Singapore. 13. UMRS 942 Inserm, Paris 75010, France Department of Biochemistry, Lariboisière Hospital, 2, Rue A. Paré, 75475, Paris, Cedex 10, France Center for Biological Resources, Lariboisière Hospital, Paris, France alexandre.mebazaa@lrb.ap-hp.fr alexandre.mebazaa@lrb.aphp.fr. 14. UMRS 942 Inserm, Paris 75010, France DHU Neurovasc Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France Paris Diderot University, Sorbonne Paris Cité, Paris 75205, France alexandre.mebazaa@lrb.ap-hp.fr alexandre.mebazaa@lrb.aphp.fr.
Abstract
BACKGROUND: Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. METHODS AND RESULTS: Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF (n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction (ρ = -0.62, P < 0.001) but less so to BNP. In addition, we observed an increase in furin activity that is positively related to the plasma levels of proBNP, NT-proBNP and BNP overproduction (all P < 0.001, all ρ > 0.88), and negatively related to the degree of proBNP glycosylation (ρ = -0.62, P < 0.001). CONCLUSION: These comprehensive results provide a paradigm for the post-translational modification of natriuretic peptides in ADHF: as proBNP glycosylation decreases, furin activity increases. This synergistically amplifies the processing of proBNP into BNP and NT-proBNP. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/. Identifier: NCT01374880. Published on behalf of the European Society of Cardiology. All rights reserved.
BACKGROUND: Increases in plasma B-type natriuretic peptide (BNP) concentrations in those with acutely decompensated heart failure (ADHF) has been mainly attributed to an increase in NPPB gene transcription. Recently, proBNP glycosylation has emerged as a potential regulatory mechanism in the production of amino-terminal (NT)-proBNP and BNP. The aim of the present study was to investigate proBNP glycosylation, and corin and furin activities in ADHF patients. METHODS AND RESULTS: Plasma levels of proBNP, NT-proBNP, BNP, as well as corin and furin concentration and activity were measured in a large cohort of 683 patients presenting with ADHF (n = 468), non-cardiac dyspnoea (non-ADHF: n = 169) and 46 patients with stable chronic heart failure (CHF); the degree of plasma proBNP glycosylation was assessed in a subset of these patients (ADHF: n = 49, non-ADHF: n = 50, CHF: n = 46). Our results showed a decrease in proBNP glycosylation in ADHF patients that paralleled NT-proBNP overproduction (ρ = -0.62, P < 0.001) but less so to BNP. In addition, we observed an increase in furin activity that is positively related to the plasma levels of proBNP, NT-proBNP and BNP overproduction (all P < 0.001, all ρ > 0.88), and negatively related to the degree of proBNP glycosylation (ρ = -0.62, P < 0.001). CONCLUSION: These comprehensive results provide a paradigm for the post-translational modification of natriuretic peptides in ADHF: as proBNP glycosylation decreases, furin activity increases. This synergistically amplifies the processing of proBNP into BNP and NT-proBNP. CLINICAL TRIAL REGISTRATION: http://clinicaltrials.gov/. Identifier: NCT01374880. Published on behalf of the European Society of Cardiology. All rights reserved.
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