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

19 Scopus citations

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

Keywords

  • Cardiovascular diseases
  • Hypertension
  • Lung
  • Pulmonary

ASJC Scopus subject areas

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

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    Hartney, J. M., Stidham, T., Goldstrohm, D. A., Oberley-Deegan, R. E., Weaver, M. R., Valnickova-Hansen, Z., Scavenius, C., Benninger, R. K. P., Leahy, K. F., Johnson, R., Gally, F., Kosmider, B., Zimmermann, A. K., Enghild, J. J., Nozik-Grayck, E., & Bowler, R. P. (2014). A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution. Circulation: Cardiovascular Genetics, 7(5), 659-666. https://doi.org/10.1161/CIRCGENETICS.113.000504