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Editorial
Complexity of molecular forms of B-type natriuretic peptide in heart failure
  1. Toshio Nishikimi1,
  2. Koichiro Kuwahara1,
  3. Yasuaki Nakagawa1,
  4. Kenji Kangawa2,
  5. Naoto Minamino3,
  6. Kazuwa Nakao1
  1. 1Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
  2. 2Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
  3. 3Department of Molecular Pharmacology, National Cerebral and Cardiovascular Center Research Institute, , Osaka, Japan
  1. Correspondence to Professor Toshio Nishikimi,  Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Shogoin-Kawara-cho 54, Sakyo-ku, Kyoto 606-8507, Japan; nishikim{at}kuhp.kyoto-u.ac.jp

https://doi.org/10.1136/heartjnl-2012-302929

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    Introduction

    In 1988, a Japanese group isolated B-type (or brain) natriuretic peptide (BNP) from porcine brain extracts by monitoring its relaxant effects on chick rectum.1 Since then studies in humans and rodents demonstrated that BNP is a cardiac hormone mainly expressed in the heart, where its concentration is considerably higher than in brain. BNP possesses a 17-amino acid ring structure containing two cysteine residues, which is essential for its biological activity. Mechanical stress, ischaemia, cytokines and neurohumoral factors, including angiotensin II, stimulate expression of BNP (figure 1),2 and levels of myocardial BNP mRNA and circulating BNP and N-terminal proBNP (NT-proBNP) are markedly increased in patients with congestive heart failure.2 BNP is therefore considered to function as an emergency defence against ventricular overload in disease states.

    Figure 1

    Schematic representation of the stimulus, signal transduction, gene, mRNA, translation, glycosylation, processing and secretion of B-type natriuretic peptide (BNP) in myocytes, and the plasma molecular forms of BNP. Mechanical stress, ischaemia, cytokines and neurohumoral factors (eg, angiotensin II and endothelin-1) stimulate gene expression of BNP via signal transduction mediated by protein kinase C and mitogen-activated protein (MAP) kinase. BNP mRNA is translated in the endoplasmic reticulum, after which preproBNP is converted to proBNP by a signal peptidase. ProBNP is post-translationally O-glycosylated within the Golgi apparatus and cleaved to BNP and NT-proBNP in equimolar fashion by furin within the trans-Golgi network. They are then transferred to secretion vesicles and secreted into the circulation via a so-called constitutive secretion pathway. ProBNP is often heavily O-glycosylated in the N-terminal region, and furin cannot easily cleave O-glycosylated proBNP when Thr71 is O-glycosylated. In the plasma, BNP is degraded to BNP [3-32] by dipeptidyl peptidase IV, after which BNP [3–32] is further degraded to BNP [4–32], BNP [5–32] and other metabolites by aminopeptidases. …

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    Footnotes

    • Funding This study was supported in part by Scientific Research Grants-in-Aid 20590837 and 23591041 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to TN); a grant (AS 232Z01302F) from the Japan Science and Technology Agency (to TN); a grant from the Suzuken Memorial Foundation (to TN) and the Intramural Research Fund of National Cerebral and Cardiovascular Center (to NM).

    • Competing interests None.

    • Contributors TN mainly wrote the manuscript. YN, KK, and NM criticised it and provided the useful discussion.

    • KN and KK are supervisors and they provided useful comments to the manuscript.

    • Provenance and peer review Not commissioned; internally peer reviewed.