ProBNP 1-108 is resistant to degradation and activates guanylyl cyclase-A with reduced potency

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Abstract

BACKGROUND: B-type natriuretic peptide (BNP) compensates for the failing heart and is synthesized as a 108-residue prohormone that is cleaved to a 32-residue C-terminal maximally active peptide. During heart failure, serum concentrations of proBNP 1-108 exceed concentrations of BNP 1-32. The aim of this study was to determine why the proBNP 1-108/BNP 1-32 ratio increases and whether proBNP 1-108 is bioactive. METHODS: Using cGMP elevation and 125I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP 1-108 and human synthetic BNP 1-32. Using receptor bioassays, we measured degradation of recombinant proBNP 1-108 and BNP 1-32 by human kidney membranes. RESULTS: ProBNP 1-108 stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP 1-32. ProBNP 1-108 bound human GC-A 35-fold less tightly than BNP 1-32. Neither proBNP 1-108 nor BNP 1-32 activated GC-B. The natriuretic peptide clearance receptor bound proBNP 1-108 3-fold less tightly than BNP 1-32. The half time for degradation of proBNP 1-108 by human kidney membranes was 2.7-fold longer than for BNP 1-32, and the time required for complete degradation was 6-fold longer. BNP 1-32 and proBNP 1-108 were best fitted by first- and second-order exponential decay models, respectively. CONCLUSIONS: ProBNP 1-108 activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP 1-108 may contribute to the increased ratio of serum proBNP 1-108 to BNP 1-32 observed in patients with congestive heart failure.

Original languageEnglish (US)
Pages (from-to)1272-1278
Number of pages7
JournalClinical chemistry
Volume57
Issue number9
DOIs
StatePublished - Sep 1 2011

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Brain Natriuretic Peptide
Degradation
Natriuretic Peptides
Peptide Receptors
atrial natriuretic factor receptor A
peptide 32
Heart Failure
Membranes
Kidney
Bioassay
Atrial Natriuretic Factor
Serum
Biological Assay
Assays
Chemical activation

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ProBNP 1-108 is resistant to degradation and activates guanylyl cyclase-A with reduced potency. / Dickey, Deborah M.; Potter, Lincoln R.

In: Clinical chemistry, Vol. 57, No. 9, 01.09.2011, p. 1272-1278.

Research output: Contribution to journalArticle

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title = "ProBNP 1-108 is resistant to degradation and activates guanylyl cyclase-A with reduced potency",
abstract = "BACKGROUND: B-type natriuretic peptide (BNP) compensates for the failing heart and is synthesized as a 108-residue prohormone that is cleaved to a 32-residue C-terminal maximally active peptide. During heart failure, serum concentrations of proBNP 1-108 exceed concentrations of BNP 1-32. The aim of this study was to determine why the proBNP 1-108/BNP 1-32 ratio increases and whether proBNP 1-108 is bioactive. METHODS: Using cGMP elevation and 125I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP 1-108 and human synthetic BNP 1-32. Using receptor bioassays, we measured degradation of recombinant proBNP 1-108 and BNP 1-32 by human kidney membranes. RESULTS: ProBNP 1-108 stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP 1-32. ProBNP 1-108 bound human GC-A 35-fold less tightly than BNP 1-32. Neither proBNP 1-108 nor BNP 1-32 activated GC-B. The natriuretic peptide clearance receptor bound proBNP 1-108 3-fold less tightly than BNP 1-32. The half time for degradation of proBNP 1-108 by human kidney membranes was 2.7-fold longer than for BNP 1-32, and the time required for complete degradation was 6-fold longer. BNP 1-32 and proBNP 1-108 were best fitted by first- and second-order exponential decay models, respectively. CONCLUSIONS: ProBNP 1-108 activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP 1-108 may contribute to the increased ratio of serum proBNP 1-108 to BNP 1-32 observed in patients with congestive heart failure.",
author = "Dickey, {Deborah M.} and Potter, {Lincoln R.}",
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T1 - ProBNP 1-108 is resistant to degradation and activates guanylyl cyclase-A with reduced potency

AU - Dickey, Deborah M.

AU - Potter, Lincoln R.

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Y1 - 2011/9/1

N2 - BACKGROUND: B-type natriuretic peptide (BNP) compensates for the failing heart and is synthesized as a 108-residue prohormone that is cleaved to a 32-residue C-terminal maximally active peptide. During heart failure, serum concentrations of proBNP 1-108 exceed concentrations of BNP 1-32. The aim of this study was to determine why the proBNP 1-108/BNP 1-32 ratio increases and whether proBNP 1-108 is bioactive. METHODS: Using cGMP elevation and 125I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP 1-108 and human synthetic BNP 1-32. Using receptor bioassays, we measured degradation of recombinant proBNP 1-108 and BNP 1-32 by human kidney membranes. RESULTS: ProBNP 1-108 stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP 1-32. ProBNP 1-108 bound human GC-A 35-fold less tightly than BNP 1-32. Neither proBNP 1-108 nor BNP 1-32 activated GC-B. The natriuretic peptide clearance receptor bound proBNP 1-108 3-fold less tightly than BNP 1-32. The half time for degradation of proBNP 1-108 by human kidney membranes was 2.7-fold longer than for BNP 1-32, and the time required for complete degradation was 6-fold longer. BNP 1-32 and proBNP 1-108 were best fitted by first- and second-order exponential decay models, respectively. CONCLUSIONS: ProBNP 1-108 activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP 1-108 may contribute to the increased ratio of serum proBNP 1-108 to BNP 1-32 observed in patients with congestive heart failure.

AB - BACKGROUND: B-type natriuretic peptide (BNP) compensates for the failing heart and is synthesized as a 108-residue prohormone that is cleaved to a 32-residue C-terminal maximally active peptide. During heart failure, serum concentrations of proBNP 1-108 exceed concentrations of BNP 1-32. The aim of this study was to determine why the proBNP 1-108/BNP 1-32 ratio increases and whether proBNP 1-108 is bioactive. METHODS: Using cGMP elevation and 125I-ANP binding assays, we measured binding and activation of individual human natriuretic peptide receptor populations by recombinant human proBNP 1-108 and human synthetic BNP 1-32. Using receptor bioassays, we measured degradation of recombinant proBNP 1-108 and BNP 1-32 by human kidney membranes. RESULTS: ProBNP 1-108 stimulated guanylyl cyclase-A (GC-A) to near-maximum activities but was 13-fold less potent than BNP 1-32. ProBNP 1-108 bound human GC-A 35-fold less tightly than BNP 1-32. Neither proBNP 1-108 nor BNP 1-32 activated GC-B. The natriuretic peptide clearance receptor bound proBNP 1-108 3-fold less tightly than BNP 1-32. The half time for degradation of proBNP 1-108 by human kidney membranes was 2.7-fold longer than for BNP 1-32, and the time required for complete degradation was 6-fold longer. BNP 1-32 and proBNP 1-108 were best fitted by first- and second-order exponential decay models, respectively. CONCLUSIONS: ProBNP 1-108 activates GC-A with reduced potency and is resistant to degradation. Reduced degradation of proBNP 1-108 may contribute to the increased ratio of serum proBNP 1-108 to BNP 1-32 observed in patients with congestive heart failure.

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