A Human Atrial Natriuretic Peptide Gene Mutation Reveals a Novel Peptide With Enhanced Blood Pressure-Lowering, Renal-Enhancing, and Aldosterone-Suppressing Actions

Paul McKie, Alessandro Cataliotti, Brenda K. Huntley, Fernando L. Martin, Timothy Mark Olson, John C Jr. Burnett

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Objectives: We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP). Background: The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP(1-28) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP. Methods: In vitro 3′,5′-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs. Results: We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP. Conclusions: These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.

Original languageEnglish (US)
Pages (from-to)1024-1032
Number of pages9
JournalJournal of the American College of Cardiology
Volume54
Issue number11
DOIs
StatePublished - Sep 8 2009

Fingerprint

Atrial Natriuretic Factor
Aldosterone
Blood Pressure
Kidney
Peptides
Mutation
Genes
Cyclic GMP
Diuretics
Amino Acids
Glomerular Filtration Rate
Guanosine Monophosphate
Renal Circulation
Renin-Angiotensin System
Action Potentials

Keywords

  • aldosterone
  • angiotensin
  • blood pressure
  • heart failure
  • kidney
  • natriuretic peptide

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

@article{25747d173db142adab4cf76855bd8f97,
title = "A Human Atrial Natriuretic Peptide Gene Mutation Reveals a Novel Peptide With Enhanced Blood Pressure-Lowering, Renal-Enhancing, and Aldosterone-Suppressing Actions",
abstract = "Objectives: We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP). Background: The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP(1-28) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP. Methods: In vitro 3′,5′-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs. Results: We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP. Conclusions: These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.",
keywords = "aldosterone, angiotensin, blood pressure, heart failure, kidney, natriuretic peptide",
author = "Paul McKie and Alessandro Cataliotti and Huntley, {Brenda K.} and Martin, {Fernando L.} and Olson, {Timothy Mark} and Burnett, {John C Jr.}",
year = "2009",
month = "9",
day = "8",
doi = "10.1016/j.jacc.2009.04.080",
language = "English (US)",
volume = "54",
pages = "1024--1032",
journal = "Journal of the American College of Cardiology",
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T1 - A Human Atrial Natriuretic Peptide Gene Mutation Reveals a Novel Peptide With Enhanced Blood Pressure-Lowering, Renal-Enhancing, and Aldosterone-Suppressing Actions

AU - McKie, Paul

AU - Cataliotti, Alessandro

AU - Huntley, Brenda K.

AU - Martin, Fernando L.

AU - Olson, Timothy Mark

AU - Burnett, John C Jr.

PY - 2009/9/8

Y1 - 2009/9/8

N2 - Objectives: We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP). Background: The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP(1-28) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP. Methods: In vitro 3′,5′-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs. Results: We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP. Conclusions: These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.

AB - Objectives: We sought to determine the physiologic actions and potential therapeutic applications of mutant atrial natriuretic peptide (mANP). Background: The cardiac hormone atrial natriuretic peptide (ANP) is a 28-amino acid (AA) peptide that consists of a 17-AA ring structure together with a 6-AA N-terminus and a 5-AA C-terminus. In a targeted scan for sequence variants within the human ANP gene, a mutation was identified that results in a 40-AA peptide consisting of native ANP(1-28) and a C-terminal extension of 12 AA. We have termed this peptide mutant ANP. Methods: In vitro 3′,5′-cyclic guanosine monophosphate (cGMP) activation in response to mANP was studied in cultured human cardiac fibroblasts known to express natriuretic peptide receptor A. The cardiorenal and neurohumoral properties of mANP compared with ANP were assessed in vivo in normal dogs. Results: We observed an incremental in vitro cGMP dose response with increasing concentrations of mANP. In vivo with high-dose mANP (33 pmol/kg/min), we observed significantly greater plasma cGMP activation, diuretic, natriuretic, glomerular filtration rate enhancing, renin-angiotensin-aldosterone system inhibiting, cardiac unloading, and blood pressure lowering properties when compared with native ANP. Low-dose mANP (2 pmol/kg/min) has natriuretic and diuretic properties without altering systemic hemodynamics compared with no natriuretic or diuretic response with low-dose native ANP. Conclusions: These studies establish that mANP activates cGMP in vitro and exerts greater and more sustained natriuretic, diuretic, glomerular filtration rate, and renal blood flow enhancing actions than native ANP in vivo.

KW - aldosterone

KW - angiotensin

KW - blood pressure

KW - heart failure

KW - kidney

KW - natriuretic peptide

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