title: MiR30-GALNT1/2 Axis-Mediated Glycosylation Contributes to the Increased Secretion of Inactive Human Prohormone for Brain Natriuretic Peptide (proBNP) From Failing Hearts.
abstract: Recent studies have shown that plasma levels of the biologically inactive prohormone for brain natriuretic peptide (proBNP) are increased in patients with heart failure. This can contribute to a reduction in the effectiveness of circulating BNP and exacerbate heart failure progression. The precise mechanisms governing the increase in proBNP remain unclear, however.
  
  
  
  We used our recently developed, highly sensitive human proBNP assay system to investigate the mechanisms underlying the increase in plasma proBNP levels. We divided 53 consecutive patients hospitalized with heart failure into 2 groups based on their aortic plasma levels of immunoreactive BNP. Patients with higher levels exhibited more severe heart failure, a higher proportion of proBNP among the immunoreactive BNP forms secreted from failing hearts, and a weaker effect of BNP as estimated from the ratio of plasma cyclic guanosine monophosphate levels to log-transformed plasma BNP levels. Glycosylation at threonines 48 and 71 of human proBNP contributed to the increased secretion of proBNP by attenuating its processing, and GalNAc-transferase (GALNT) 1 and 2 mediated the glycosylation-regulated increase in cardiac human proBNP secretion. Cardiac GALNT1 and 2 expression was suppressed by microRNA (miR)-30, which is abundantly expressed in the myocardium of healthy hearts, but is suppressed in failing hearts.
  
  
  
  We have elucidated a novel miR-30-GALNT1/2 axis whose dysregulation increases the proportion of inactive proBNP secreted by the heart and impairs the compensatory actions of BNP during the progression of heart failure.
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan nishikim@kuhp.kyoto-u.ac.jp kuwa@kuhp.kyoto-u.ac.jp.
authors.forename: Toshio
authors.initials: T
authors.lastname: Nishikimi
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan nishikim@kuhp.kyoto-u.ac.jp kuwa@kuhp.kyoto-u.ac.jp.|Department of Cardiovascular Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kuwahara
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Aoi
authors.initials: A
authors.lastname: Fujishima
authors.affiliation: Department of Biology Chemistry, Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Oka
authors.affiliation: Toyosato Hospital, Toyosato, Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Tsutamoto
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Kinoshita
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.|Department of Primary Care and Emergency Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kosai
authors.initials: K
authors.lastname: Cho
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Inazumi
authors.affiliation: Diagnostics Division, Shionogi & Co., Ltd, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Okamoto
authors.affiliation: Division of Cardiocirculatory Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, Japan.
authors.forename: Motohiro
authors.initials: M
authors.lastname: Nishida
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Kato
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Fukushima
authors.affiliation: Department of Cell Growth and Differentiation, Center for iPS Cell Research and Application, Kyoto University, Kyoto, Japan.
authors.forename: Jun K
authors.initials: JK
authors.lastname: Yamashita
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Wino J
authors.initials: WJ
authors.lastname: Wijnen
authors.affiliation: Department of Experimental Cardiology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Esther E
authors.initials: EE
authors.lastname: Creemers
authors.affiliation: National Cerebral and Cardiovascular Center Research Institute, Suita, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kangawa
authors.affiliation: Omics Research Center, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Naoto
authors.initials: N
authors.lastname: Minamino
authors.affiliation: Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
authors.affiliation: Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000368:Aged; D000818:Animals; D000831:Animals, Newborn; D001013:Aorta, Thoracic / Q000378:metabolism*; D015415:Biomarkers / Q000097:blood; D015153:Blotting, Western; D002478:Cells, Cultured; D002850:Chromatography, Gel; D004195:Disease Models, Animal; D018450:Disease Progression; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D006031:Glycosylation; D006333:Heart Failure / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D017350:N-Acetylgalactosaminyltransferases / Q000096:biosynthesis / Q000235:genetics*; D020097:Natriuretic Peptide, Brain / Q000097:blood*; D010446:Peptide Fragments / Q000097:blood*; D011498:Protein Precursors; D051381:Rats; D020303:Rats, Inbred Dahl; D060888:Real-Time Polymerase Chain Reaction; D012189:Retrospective Studies; D015398:Signal Transduction; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D015415:Biomarkers; D035683:MicroRNAs; D017350:N-Acetylgalactosaminyltransferases; D020097:Natriuretic Peptide, Brain; D010446:Peptide Fragments; D011498:Protein Precursors; D000097763:Polypeptide N-acetylgalactosaminyltransferase; C550735:MIRN301A microRNA, human; C546086:MIRN30b microRNA, human; C109794:pro-brain natriuretic peptide (1-76)
keywords: microRNA; natriuretic peptide; signal transduction