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.
  
  
  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.
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: John M
authors.initials: JM
authors.lastname: Hartney
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Timothy
authors.initials: T
authors.lastname: Stidham
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: David A
authors.initials: DA
authors.lastname: Goldstrohm
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Oberley-Deegan
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Michael R
authors.initials: MR
authors.lastname: Weaver
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Valnickova-Hansen
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Carsten
authors.initials: C
authors.lastname: Scavenius
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Richard K P
authors.initials: RK
authors.lastname: Benninger
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Katelyn F
authors.initials: KF
authors.lastname: Leahy
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Richard
authors.initials: R
authors.lastname: Johnson
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Fabienne
authors.initials: F
authors.lastname: Gally
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Beata
authors.initials: B
authors.lastname: Kosmider
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Angela K
authors.initials: AK
authors.lastname: Zimmermann
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.).
authors.forename: Eva
authors.initials: E
authors.lastname: Nozik-Grayck
authors.affiliation: From the Department of Medicine, National Jewish Health, Denver, CO (J.M.H., D.A.G., R.E.O.-D., M.R.W., K.F.L., F.G., B.K., R.P.B.); Integrated Department of Immunology, University of Colorado, Denver (J.M.H.); Departments of Pediatrics (T.S., R.K.P.B., R.J., E.N.-G.) and Bioengineering (R.K.P.B.), University of Colorado School of Medicine, Aurora; Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark (Z.V.-H., C.S., J.J.E.); and Institut de Biologie du Developpement de Marseille Luminy, Aix-Marseille University, Marseille, France (A.K.Z.). bowlerr@njhealth.org.
authors.forename: Russell P
authors.initials: RP
authors.lastname: Bowler
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000737:chemistry; D001120:Arginine / Q000737:chemistry; D001992:Bronchoalveolar Lavage Fluid; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005998:Glycine / Q000737:chemistry; D006493:Heparin / Q000737:chemistry; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012685:Sepharose / Q000737:chemistry; D017422:Sequence Analysis, DNA; D013482:Superoxide Dismutase / Q000235:genetics*
chemical_list: D000975:Antioxidants; D006493:Heparin; D012685:Sepharose; D001120:Arginine; C441642:SOD3 protein, human; C499090:Sod3 protein, mouse; D013482:Superoxide Dismutase; D005998:Glycine
keywords: cardiovascular diseases; hypertension, pulmonary; lung
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