Secretion of glycosylated pro-B-type natriuretic peptide from normal cardiomyocytes

Jason M. Tonne, Jarryd M. Campbell, Alessandro Cataliotti, Seiga Ohmine, Tayaramma Thatava, Toshie Sakuma, Fima Macheret, Brenda K. Huntley, John C. Burnett, Yasuhiro Ikeda

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41 Scopus citations

Abstract

BACKGROUND: B-type natriuretic peptide (BNP), a key cardiac hormone in cardiorenal homeostasis, is produced as a 108 amino acid prohormone, proBNP1-108, which is converted to a biologically active peptide BNP1-32 and an inactive N-terminal (NT)-proBNP1-76. The widely accepted model is that the normal heart releases a proteolytically processed BNP1-32 and NTproBNP, whereas the diseased heart secretes high amounts of unprocessed/glycosylated proBNP1-108 or inappropriately processed BNPs. In contrast, circulating proBNP1-108 has recently been identified in healthy individuals, indicating that the normal heart also secretes unprocessed proBNP1-108. However, the mechanism of proBNP1-108 secretion from the normal heart remains elusive. Our goal was to determine the molecular mechanisms underlying proBNP1-108 intracellular trafficking and secretion from the normal heart. METHODS: We expressed preproBNP in cardiomyocytes, and determined the subcellular localization and dominant intracellular and extracellular forms of BNP. RESULTS: Intracellular immunoreactive BNPs were first accumulated in the Golgi apparatus, and then distributed throughout the cytoplasm as secretory vesicles. The predominant intracellular form of BNP was nonglycosylated proBNP1-108, rather than BNP1-32. Glycosylated proBNP1-108, but not non-glycosylated proBNP1-108, was detected as the major extracellular form in the culture supernatants of preproBNP-expressing cell lines and primary human cardiomyocytes. Ablation of O-glycosylation of proBNP1-108 at T71 residue, near the convertase recognition site, reduced the extracellular proBNP1-108 and increased extracellular BNP1-32. CONCLUSIONS: Intracellular proBNP trafficking occurs through a conventional Golgi-endoplasmic reticulum pathway. Glycosylation of proBNP1-108 controls the stability and processing of extracellular proBNP1-108. Our data establish a new BNP secretion model in which the normal cardiac cells secrete glycosylated proBNP1-108.

Original languageEnglish (US)
Pages (from-to)864-873
Number of pages10
JournalClinical chemistry
Volume57
Issue number6
DOIs
StatePublished - Jun 2011

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Biochemistry, medical

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    Tonne, J. M., Campbell, J. M., Cataliotti, A., Ohmine, S., Thatava, T., Sakuma, T., Macheret, F., Huntley, B. K., Burnett, J. C., & Ikeda, Y. (2011). Secretion of glycosylated pro-B-type natriuretic peptide from normal cardiomyocytes. Clinical chemistry, 57(6), 864-873. https://doi.org/10.1373/clinchem.2010.157438