A Common Polymorphism in EC-SOD Affects Cardiopulmonary Disease Risk by Altering Protein Distribution

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • John M Hartney, Department of Medicine, National Jewish Health & Integrated Department of Immunology, University of Colorado Denver, Denver, CO., Unknown
  • Timothy Stidham, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO., Unknown
  • David A Goldstrohm, Department of Medicine, National Jewish Health, Denver, CO., Unknown
  • Rebecca E Oberley-Deegan, Department of Medicine, National Jewish Health, Denver, CO., Unknown
  • Michael R Weaver, Department of Medicine, National Jewish Health, Denver, CO., Unknown
  • Zuzana Valnickova-Hansen, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark., Unknown
  • Carsten Scavenius
  • Richard K P Benninger, Department of Pediatrics & Department of Bioengineering, University of Colorado School of Medicine, Aurora, CO., Unknown
  • Katelyn F Leahy, Department of Medicine, National Jewish Health, Denver, CO., Unknown
  • Richard Johnson, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
  • ,
  • Fabienne Gally, Department of Medicine, National Jewish Health, Denver, CO., Unknown
  • Beata Kosmider, Department of Medicine, National Jewish Health, Denver, CO., Unknown
  • Angela K Zimmermann, Institut de Biologie du Developpement de Marseille Luminy (IBDML), Aix-Marseille University, Marseille, France., Unknown
  • Jan J Enghild
  • Eva Nozik-Grayck, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO., Unknown
  • Russell P Bowler, Department of Medicine, National Jewish Health, Denver, CO Bowlerr@njhealth.org., Unknown

BACKGROUND: -The enzyme extracellular superoxide dismutase (EC-SOD; SOD3) is a major antioxidant defense in lung and vasculature. A nonsynonomous single nucleotide polymorphism (SNP) in EC-SOD (rs1799895) leads to an arginine to glycine (Arg→Gly) amino acid substitution at position 213 (R213G) in the heparin-binding domain (HBD). In recent human genetic association studies, this SNP 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 HBD, we created an analogous R213G SNP knockin mouse. The R213G SNP did not change enzyme activity, but shifted the distribution of EC-SOD from lung and vascular tissue to extracellular fluid (e.g. bronchoalveolar lavage fluid (BALF) 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
JournalCirculation. Cardiovascular Genetics (Online)
Volume7
Issue6
Pages (from-to)659-666
Number of pages8
ISSN1942-3268
DOIs
Publication statusPublished - 1 Aug 2014

See relations at Aarhus University Citationformats

ID: 81882431