Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure

Post-translational modifications enhance NT-proBNP and BNP production in acute decompensated heart failure

Vodovar N1, Séronde MF2, Laribi S3, Gayat E4, Lassus J5, Boukef R6, Nouira S6, Manivet P7, Samuel JL8, Logeart D9, Ishihara S10, Cohen Solal A9, Januzzi JL Jr11, Richards AM12, Launay JM13, Mebazaa A14; GREAT NetworkEur Heart J. 2014 Dec 21;35(48):3434-41.

Source : 1UMRS 942 Inserm, Paris 75010, France DHU FIRE; 2UMRS 942 Inserm, Paris 75010, France Department of Cardiology, EA3920, University Hospital Jean Minjoz, Besançon, France; 3UMRS 942 Inserm, Paris 75010, France Department of Emergency Medicine, Lariboisière Hospital, Paris, France DHU Neurovasc; 4UMRS 942 Inserm, Paris 75010, France DHU Neurovasc Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France; 5Heart and Lung Center, Division of Cardiology, Helsinki University Central Hospital, Helsinki, Finland; 6Emergency Department and Research Unit UR06SP21, Fattouma Bourguiba University Hospital, Monastir, Tunisia; 7UMRS 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; 8UMRS 942 Inserm, Paris 75010, France Department of Anesthesiology and Intensive Care, Lariboisière Hospital, 2, Rue A. Paré, 75475 Paris, Cedex 10, France; 9UMRS 942 Inserm, Paris 75010, France DHU FIRE Department of Cardiology, Lariboisière Hospital, Paris, France Paris Diderot University, Sorbonne Paris Cité, Paris 75205, France; 10UMRS 942 Inserm, Paris 75010, France Cardiology and Intensive Care Unit, Nippon Medical School Musashi-Kosugi Hospital, Kanagawa, Japan; 11Cardiology Division, Massachusetts General Hospital, Boston, MA, USA; 12University of Otago, Christchurch, New Zealand National University Health System, Singarpore, Singapore; 13UMRS 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; 14UMRS 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.

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 heartfailure (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 (? = -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 BNPoverproduction (all P < 0.001, all ? > 0.88), and negatively related to the degree of proBNP glycosylation (? = -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.