ArticleCirculation. Cardiovascular genetics2014
A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution.
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Article in Circulation. Cardiovascular genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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30citing papers in PubMed
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Who cites it
30 citing papers in PubMed, 38 citations in OpenAlex.
- R213G-Mediated Redistribution of EC-SOD Protects Against Sugen-Hypoxia Pulmonary Hypertension in Mice.Pulmonary circulation · 2026Article
- Extracellular Superoxide Dismutase in Acute Respiratory Distress Syndrome: Pathogenic Mechanisms and Therapeutic Implications.Antioxidants (Basel, Switzerland) · 2026Review
- Vascular EC-SOD limits the accumulation, proinflammatory profibrotic reprogramming, and hyaluronan binding of interstitial macrophages in hypoxia.American journal of physiology. Lung cellular and molecular physiology · 2025Article
- Increased Circulating Extracellular Superoxide Dismutase Attenuates Platelet-Neutrophil Interactions.American journal of respiratory cell and molecular biology · 2025Article
- Redistribution of SOD3 expression due to R213G polymorphism affects pulmonary interstitial macrophage reprogramming in response to hypoxia.Physiological genomics · 2024Article
- Exploration of SOD3 from gene to therapeutic prospects: a brief review.Molecular biology reports · 2024Review
- Lung EC-SOD Overexpression Prevents Hypoxia-Induced Platelet Activation and Lung Platelet Accumulation.Antioxidants (Basel, Switzerland) · 2024Article
- Release of extracellular superoxide dismutase into alveolar fluid protects against acute lung injury and inflammation inAmerican journal of physiology. Lung cellular and molecular physiology · 2023Article
- Extracellular superoxide dismutase (EC-SOD) R213G variant reduces mitochondrial ROS and preserves mitochondrial function in bleomycin-induced lung injury: EC-SOD R213G variant and intracellular redox regulation.Advances in redox research · 2022Article
- Metabolism, Mitochondrial Dysfunction, and Redox Homeostasis in Pulmonary Hypertension.Antioxidants (Basel, Switzerland) · 2022Review
- Association among extracellular superoxide dismutase genotype, plasma concentration, and comorbidity in the very old and centenarians.Scientific reports · 2021Article
- MicroRNA regulation postbleomycin due to the R213G extracellular superoxide dismutase variant is predicted to suppress inflammatory and immune pathways.Physiological genomics · 2020Article
- Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise.Redox biology · 2020Review
- Extracellular Superoxide Dismutase Regulates Early Vascular Hyaluronan Remodeling in Hypoxic Pulmonary Hypertension.Scientific reports · 2020Article
- Redistribution of EC-SOD resolves bleomycin-induced inflammationFASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2019Article
- Redox Biology of Peroxisome Proliferator-Activated Receptor-γ in Pulmonary Hypertension.Antioxidants & redox signaling · 2019Review
- Oxidative Toxicology of Bleomycin: Role of the Extracellular Redox Environment.Current opinion in toxicology · 2019Article
- Genetic Polymorphisms Affecting IDO1 or IDO2 Activity Differently Associate With Aspergillosis in Humans.Frontiers in immunology · 2019Article
- R213G polymorphism in SOD3 protects against bleomycin-induced inflammation and attenuates induction of proinflammatory pathways.Physiological genomics · 2018Article
- Redistribution of Extracellular Superoxide Dismutase Causes Neonatal Pulmonary Vascular Remodeling and PH but Protects Against Experimental Bronchopulmonary Dysplasia.Antioxidants (Basel, Switzerland) · 2018Article
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Authors and funding
16 authors at 2 institutions in 2 countries.
John M HartneyFrom 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.).
Timothy StidhamFrom 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.).
David A GoldstrohmFrom 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.).
Rebecca E Oberley-DeeganFrom 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.).
Michael R WeaverFrom 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.).
Zuzana Valnickova-HansenFrom 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.).
Carsten ScaveniusFrom 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.).
Richard K P BenningerFrom 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.).
Katelyn F LeahyFrom 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.).
Richard JohnsonFrom 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.).
Fabienne GallyFrom 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.).
Beata KosmiderFrom 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.).
Angela K ZimmermannFrom 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.).
Jan J EnghildFrom 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.).
Eva Nozik-GrayckFrom 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.).
Russell P BowlerFrom 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.
University of Colorado Denver · USAarhus University · DK
Funding
CTSA INFRASTRUCTURE FOR PEDIATRIC RESEARCHUL1RR025780 · NCRR · UNIVERSITY OF COLORADO DENVER · PI SOKOL, RONALD J. · 2008 to 2011
$61.3MColorado Clinical and Translational Sciences InstituteUL1TR001082 · NCATS · UNIVERSITY OF COLORADO DENVER · PI SOKOL, RONALD J. · 2013 to 2017
$48.0MImpact of Insufficient Vascular EC-SOD in Pulmonary HypertensionR01HL086680 · NHLBI · UNIVERSITY OF COLORADO DENVER · PI NOZIK, EVA S. · 2008 to 2017
$4.7MInvestigating the role of the R213G SOD3 polymorphism in lung diseaseR01HL111288 · NHLBI · NATIONAL JEWISH HEALTH · PI BOWLER, RUSSELL PAUL · 2012 to 2015
$1.1MMulti-cellular interactions and dynamics underlying pancreatic islet functionR00DK085145 · NIDDK · UNIVERSITY OF COLORADO DENVER · PI BENNINGER, RICHARD KP · 2011 to 2013
$737kREGULATION OF EXTRACELLULAR SUPEROXIDE DISMUTASE BY PROTK08HL004407 · NHLBI · NATIONAL JEWISH HEALTH · PI BOWLER, RUSSELL PAUL · 2000 to 2004
$618kNCATS NIH HHS UL1 TR001082NCRR NIH HHS UL1 RR025780NHLBI NIH HHS HL086680NHLBI NIH HHS HL111288NHLBI NIH HHS K08 HL004407NHLBI NIH HHS R01 HL086680NHLBI NIH HHS R01 HL111288NIDDK NIH HHS R00 DK085145
Abstract
backgroundThe 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
resultsCapitalizing 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).
conclusionsWe 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.
Indexed as
Polymorphism, Single NucleotideAnimalsAntioxidantsArginineBronchoalveolar Lavage FluidGenetic Predisposition to DiseaseGenotypeGlycineHeparinHumansHypertension, PulmonaryLungMiceMice, Inbred C57BLMice, TransgenicRisk FactorsAntioxidantsArginineGlycineHeparinSepharoseSOD3 protein, humanSod3 protein, mouseSuperoxide Dismutasecardiovascular diseaseshypertension, pulmonarylung
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