A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution

John M. Hartney, Timothy Stidham, David A. Goldstrohm, Rebecca E. Oberley-Deegan, Michael R. Weaver, Zuzana Valnickova-Hansen, Carsten Scavenius, Richard K.P. Benninger, Katelyn F. Leahy, Richard Johnson, Fabienne Gally, Beata Kosmider, Angela K. Zimmermann, Jan J. Enghild, Eva Nozik-Grayck, Russell P. Bowler

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

Background: The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease.Methods and Results-Capitalizing on the complete sequence homology between human and mouse in the heparin-binding domain, we created an analogous R213G single-nucleotide polymorphism knockin mouse. The R213G single-nucleotide polymorphism did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (eg, bronchoalveolar lavage fluid and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension).Conclusions: We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.

Original languageEnglish (US)
Pages (from-to)659-666
Number of pages8
JournalCirculation: Cardiovascular Genetics
Volume7
Issue number5
DOIs
StatePublished - Oct 1 2014

Fingerprint

Lung Diseases
Superoxide Dismutase
Single Nucleotide Polymorphism
Extracellular Fluid
Proteins
Lung
Heparin
Cardiovascular Diseases
Pulmonary Circulation
Bronchoalveolar Lavage Fluid
Medical Genetics
Genetic Association Studies
Lung Injury
Enzymes
Amino Acid Substitution
Sequence Homology
Vascular Diseases
Pulmonary Hypertension
Glycine
Blood Vessels

Keywords

  • Cardiovascular diseases
  • Hypertension
  • Lung
  • Pulmonary

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Cite this

A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution. / Hartney, John M.; Stidham, Timothy; Goldstrohm, David A.; Oberley-Deegan, Rebecca E.; Weaver, Michael R.; Valnickova-Hansen, Zuzana; Scavenius, Carsten; Benninger, Richard K.P.; Leahy, Katelyn F.; Johnson, Richard; Gally, Fabienne; Kosmider, Beata; Zimmermann, Angela K.; Enghild, Jan J.; Nozik-Grayck, Eva; Bowler, Russell P.

In: Circulation: Cardiovascular Genetics, Vol. 7, No. 5, 01.10.2014, p. 659-666.

Research output: Contribution to journalArticle

Hartney, JM, Stidham, T, Goldstrohm, DA, Oberley-Deegan, RE, Weaver, MR, Valnickova-Hansen, Z, Scavenius, C, Benninger, RKP, Leahy, KF, Johnson, R, Gally, F, Kosmider, B, Zimmermann, AK, Enghild, JJ, Nozik-Grayck, E & Bowler, RP 2014, 'A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution', Circulation: Cardiovascular Genetics, vol. 7, no. 5, pp. 659-666. https://doi.org/10.1161/CIRCGENETICS.113.000504
Hartney, John M. ; Stidham, Timothy ; Goldstrohm, David A. ; Oberley-Deegan, Rebecca E. ; Weaver, Michael R. ; Valnickova-Hansen, Zuzana ; Scavenius, Carsten ; Benninger, Richard K.P. ; Leahy, Katelyn F. ; Johnson, Richard ; Gally, Fabienne ; Kosmider, Beata ; Zimmermann, Angela K. ; Enghild, Jan J. ; Nozik-Grayck, Eva ; Bowler, Russell P. / A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution. In: Circulation: Cardiovascular Genetics. 2014 ; Vol. 7, No. 5. pp. 659-666.
@article{6727faed21b84a66a3902755b4dc23c1,
title = "A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution",
abstract = "Background: The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease.Methods and Results-Capitalizing on the complete sequence homology between human and mouse in the heparin-binding domain, we created an analogous R213G single-nucleotide polymorphism knockin mouse. The R213G single-nucleotide polymorphism did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (eg, bronchoalveolar lavage fluid and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension).Conclusions: We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.",
keywords = "Cardiovascular diseases, Hypertension, Lung, Pulmonary",
author = "Hartney, {John M.} and Timothy Stidham and Goldstrohm, {David A.} and Oberley-Deegan, {Rebecca E.} and Weaver, {Michael R.} and Zuzana Valnickova-Hansen and Carsten Scavenius and Benninger, {Richard K.P.} and Leahy, {Katelyn F.} and Richard Johnson and Fabienne Gally and Beata Kosmider and Zimmermann, {Angela K.} and Enghild, {Jan J.} and Eva Nozik-Grayck and Bowler, {Russell P.}",
year = "2014",
month = "10",
day = "1",
doi = "10.1161/CIRCGENETICS.113.000504",
language = "English (US)",
volume = "7",
pages = "659--666",
journal = "Circulation. Genomic and precision medicine",
issn = "1942-325X",
publisher = "Lippincott Williams and Wilkins Ltd.",
number = "5",

}

TY - JOUR

T1 - A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution

AU - Hartney, John M.

AU - Stidham, Timothy

AU - Goldstrohm, David A.

AU - Oberley-Deegan, Rebecca E.

AU - Weaver, Michael R.

AU - Valnickova-Hansen, Zuzana

AU - Scavenius, Carsten

AU - Benninger, Richard K.P.

AU - Leahy, Katelyn F.

AU - Johnson, Richard

AU - Gally, Fabienne

AU - Kosmider, Beata

AU - Zimmermann, Angela K.

AU - Enghild, Jan J.

AU - Nozik-Grayck, Eva

AU - Bowler, Russell P.

PY - 2014/10/1

Y1 - 2014/10/1

N2 - Background: The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease.Methods and Results-Capitalizing on the complete sequence homology between human and mouse in the heparin-binding domain, we created an analogous R213G single-nucleotide polymorphism knockin mouse. The R213G single-nucleotide polymorphism did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (eg, bronchoalveolar lavage fluid and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension).Conclusions: We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.

AB - Background: The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single-nucleotide polymorphism in EC-SOD (rs1799895) leads to an arginine to glycine amino acid substitution at position 213 (R213G) in the heparin-binding domain. In recent human genetic association studies, this single-nucleotide polymorphism attenuates the risk of lung disease, yet paradoxically increases the risk of cardiovascular disease.Methods and Results-Capitalizing on the complete sequence homology between human and mouse in the heparin-binding domain, we created an analogous R213G single-nucleotide polymorphism knockin mouse. The R213G single-nucleotide polymorphism did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (eg, bronchoalveolar lavage fluid and plasma). This shift reduces susceptibility to lung disease (lipopolysaccharide-induced lung injury) and increases susceptibility to cardiopulmonary disease (chronic hypoxic pulmonary hypertension).Conclusions: We conclude that EC-SOD provides optimal protection when localized to the compartment subjected to extracellular oxidative stress: thus, the redistribution of EC-SOD from the lung and pulmonary circulation to the extracellular fluids is beneficial in alveolar lung disease but detrimental in pulmonary vascular disease. These findings account for the discrepant risk associated with R213G in humans with lung diseases compared with cardiovascular diseases.

KW - Cardiovascular diseases

KW - Hypertension

KW - Lung

KW - Pulmonary

UR - http://www.scopus.com/inward/record.url?scp=84925354176&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84925354176&partnerID=8YFLogxK

U2 - 10.1161/CIRCGENETICS.113.000504

DO - 10.1161/CIRCGENETICS.113.000504

M3 - Article

C2 - 25085920

AN - SCOPUS:84925354176

VL - 7

SP - 659

EP - 666

JO - Circulation. Genomic and precision medicine

JF - Circulation. Genomic and precision medicine

SN - 1942-325X

IS - 5

ER -