ProB-type natriuretic peptide-1-108 processing and degradation in human heart failure

Brenda K. Huntley, Sharon M. Sandberg, Denise M. Heublein, S Jeson Sangaralingham, John C Jr. Burnett, Tomoko Ichiki

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Background-We have reported that proB-type natriuretic peptide (BNP)-1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared with normal. Because BNP1-32 is deficient whereas proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results-We measured circulating molecular forms, including BNP1-32, proBNP1-108, and N-terminalproBNP, and all were significantly higher in patients with HF when compared with that in normals. Fresh serum samples from normals or patients with HF were incubated with or without exogenous nonglycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag proBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 minutes in normal serum, persisted for 15 minutes, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples, and the degradation pattern differed depending on left ventricular function. The 5-minute processed forms from both normal and HF serums were active and generated cGMP via guanylyl cyclase-A receptors; however, the 180-minute samples were not active. The proBNP1-108 processing enzyme corin and BNP-degrading enzyme dipeptidyl peptidase-4 were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions-Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms were altered but complete in HF, which may contribute to the pathophysiology of HF.

Original languageEnglish (US)
Pages (from-to)89-97
Number of pages9
JournalCirculation: Heart Failure
Volume8
Issue number1
DOIs
StatePublished - 2015

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Natriuretic Peptides
Heart Failure
Serum
Pro-BNP1-108
Dipeptidyl Peptidase 4
Enzymes
Left Ventricular Function
Histidine

Keywords

  • B-type natriuretic peptide
  • Enzymes
  • Heart failure

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

ProB-type natriuretic peptide-1-108 processing and degradation in human heart failure. / Huntley, Brenda K.; Sandberg, Sharon M.; Heublein, Denise M.; Sangaralingham, S Jeson; Burnett, John C Jr.; Ichiki, Tomoko.

In: Circulation: Heart Failure, Vol. 8, No. 1, 2015, p. 89-97.

Research output: Contribution to journalArticle

Huntley, Brenda K. ; Sandberg, Sharon M. ; Heublein, Denise M. ; Sangaralingham, S Jeson ; Burnett, John C Jr. ; Ichiki, Tomoko. / ProB-type natriuretic peptide-1-108 processing and degradation in human heart failure. In: Circulation: Heart Failure. 2015 ; Vol. 8, No. 1. pp. 89-97.
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T1 - ProB-type natriuretic peptide-1-108 processing and degradation in human heart failure

AU - Huntley, Brenda K.

AU - Sandberg, Sharon M.

AU - Heublein, Denise M.

AU - Sangaralingham, S Jeson

AU - Burnett, John C Jr.

AU - Ichiki, Tomoko

PY - 2015

Y1 - 2015

N2 - Background-We have reported that proB-type natriuretic peptide (BNP)-1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared with normal. Because BNP1-32 is deficient whereas proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results-We measured circulating molecular forms, including BNP1-32, proBNP1-108, and N-terminalproBNP, and all were significantly higher in patients with HF when compared with that in normals. Fresh serum samples from normals or patients with HF were incubated with or without exogenous nonglycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag proBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 minutes in normal serum, persisted for 15 minutes, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples, and the degradation pattern differed depending on left ventricular function. The 5-minute processed forms from both normal and HF serums were active and generated cGMP via guanylyl cyclase-A receptors; however, the 180-minute samples were not active. The proBNP1-108 processing enzyme corin and BNP-degrading enzyme dipeptidyl peptidase-4 were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions-Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms were altered but complete in HF, which may contribute to the pathophysiology of HF.

AB - Background-We have reported that proB-type natriuretic peptide (BNP)-1-108 circulates and is processed to mature BNP1-32 in human blood. Building on these findings, we sought to determine whether proBNP1-108 processed forms in normal circulation are biologically active and stimulate cGMP, and whether proBNP1-108 processing and activity are altered in human heart failure (HF) compared with normal. Because BNP1-32 is deficient whereas proBNP1-108 is abundant in HF, we hypothesize that proBNP1-108 processing and degradation are impaired in HF patients ex vivo. Methods and Results-We measured circulating molecular forms, including BNP1-32, proBNP1-108, and N-terminalproBNP, and all were significantly higher in patients with HF when compared with that in normals. Fresh serum samples from normals or patients with HF were incubated with or without exogenous nonglycosylated proBNP1-108 tagged with 6 C-terminal Histidines to facilitate peptide isolation. His-tag proBNP1-108 was efficiently processed into BNP1-32/3-32 at 5 minutes in normal serum, persisted for 15 minutes, then disappeared. Delayed processing of proBNP1-108 was observed in HF samples, and the degradation pattern differed depending on left ventricular function. The 5-minute processed forms from both normal and HF serums were active and generated cGMP via guanylyl cyclase-A receptors; however, the 180-minute samples were not active. The proBNP1-108 processing enzyme corin and BNP-degrading enzyme dipeptidyl peptidase-4 were reduced in HF versus normal, perhaps contributing to differential BNP metabolism in HF. Conclusions-Exogenous proBNP1-108 is processed into active BNP1-32 and ultimately degraded in normal circulation. The processing and degradation of BNP molecular forms were altered but complete in HF, which may contribute to the pathophysiology of HF.

KW - B-type natriuretic peptide

KW - Enzymes

KW - Heart failure

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