Genomes and Genes
Extracellular superoxide induces Egr-1 in the hypoxic pulmonary artery
Principal Investigator: Eva Nozik-Grayck
Affiliation: University of Colorado Denver
Abstract: DESCRIPTION (provided by applicant): PA vascular remodeling with pulmonary hypertension is a life-threatening complication in infants and children with hypoxic lung diseases. A further understanding of this process is essential to develop new strategies aimed at reducing the severity of pulmonary hypertension in these individuals. Accumulating evidence indicates that reactive oxygen species (ROS), including superoxide (O2-) generated via NADPH oxidase, contribute to vascular remodeling. Extracellular oxidant/antioxidant homeostasis is maintained by the extracellular isoform of superoxide dismutase (EC-SOD), which is highly expressed in the vessel wall. The proposal tests the hypothesis that hypoxia disrupts the balance between the production of extracellular O2- by NADPH oxidase and its clearance by EC-SOD in the PA. We further hypothesize that excess extracellular O2- generated in the hypoxic lung upregulate a hypoxia-inducible and redox-sensitive transcription factor, early growth response-1 (Egr-1), which, in turn, stimulates Egr-1-responsive genes important in causing neonatal chronic hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension. Aim 1 will use PA segments isolated from chronically hypoxic calves and mice and in vitro pulmonary artery vascular cells isolated from the neonatal calf to evaluate production of reactive oxygen species and expression and activity of EC-SOD. Aim 2 will use chronically hypoxic mice overexpressing and lacking EC-SOD as well as mice lacking gp91phox subunit of NADPH oxidase to provide in vivo molecular and pharmacologic evidence that extracellular O2- regulates critical hypoxia-responsive genes and contributes to chronic hypoxia-induced pulmonary vascular remodeling and pulmonary hypertension in the developing lung. To complement this model, in Aim 3, we will use the PA adventitial fibroblast isolated from the neonatal calf as a highly relevant model system for in vitro experiments to test the effects of hypoxia-induced extracellular O2- on the expression of the redox-sensitive transcription factor Egr-1. The study of chronic hypoxia as a stimulus for pulmonary vascular remodeling and pulmonary hypertension is compelling, as hypoxia is a common feature of diverse lung diseases. Thus, by advancing our knowledge base and testing new therapeutic approaches in animal models, we will provide a solid foundation for future human clinical trials in a range of scenarios associated with hypoxic lung diseases to improve health outcome for patients with these difficult and serious problems. PROJECT NARRATIVE: Hypoxia complicates severe lung diseases in infants and children, and the development of pulmonary vascular remodeling and pulmonary hypertension in these patients leads to right heart failure, greatly increasing morbidity and mortality. This proposal tests whether an imbalance in production and clearance of extracellular superoxide contributes to the structural remodeling in chronic hypoxic pulmonary hypertension. This proposal will provide the basis for future human clinical trials in a range of scenarios associated with hypoxic lung diseases to improve health outcome for pediatric patients with these difficult and serious problems.
Funding Period: ----------------2007 - ---------------2012-
more information: NIH RePORT
- Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodelingEva Nozik-Grayck
Department of Pediatrics, Univ of Colorado, Denver, 4200 E 9th Ave, B131, Denver, CO 80262, USA
Am J Physiol Lung Cell Mol Physiol 295:L422-30. 2008..These data provide the first evidence that EC-SOD activity is disrupted in chronic hypoxia, and increased EC-SOD activity can attenuate chronic hypoxic PH by limiting the hypoxic upregulation of redox-sensitive genes...
- The adventitia: essential regulator of vascular wall structure and functionKurt R Stenmark
Division of Pediatric Critical Care, University of Colorado Denver, Aurora, Colorado 80045, USA
Annu Rev Physiol 75:23-47. 2013..This review presents the current evidence demonstrating that the adventitia acts as a key regulator of vascular wall function and structure from the outside in...
- Superoxide dismutase mimetic, MnTE-2-PyP, attenuates chronic hypoxia-induced pulmonary hypertension, pulmonary vascular remodeling, and activation of the NALP3 inflammasomeLeah R Villegas
Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA
Antioxid Redox Signal 18:1753-64. 2013....
- A potential role for reactive oxygen species and the HIF-1alpha-VEGF pathway in hypoxia-induced pulmonary vascular leakDavid C Irwin
University of Colorado Health Science Center, School of Medicine, Denver, CO 80262, USA
Free Radic Biol Med 47:55-61. 2009..Our data suggest that hypoxia-induced permeability is due, in part, to the ROS-HIF-1alpha-VEGF pathway...
- Pathogenesis of allergic airway inflammationDevendra K Agrawal
Center for Clinical and Translational Science, Creighton University School of Medicine, Criss II, Room 510, Omaha, NE 68178, USA
Curr Allergy Asthma Rep 10:39-48. 2010..In this review, we discuss the current information on the pathogenesis of allergic airway inflammation and potential immunotherapy, which could be beneficial in the treatment of airway inflammation, allergy, and asthma...
- Lung extracellular superoxide dismutase overexpression lessens bleomycin-induced pulmonary hypertension and vascular remodelingZachary Van Rheen
Department of Pediatrics, University of Colorado, Aurora, CO 80045, USA
Am J Respir Cell Mol Biol 44:500-8. 2011....
- Peroxisome proliferator-activated receptor-g agonist treatment increases septation and angiogenesis and decreases airway hyperresponsiveness in a model of experimental neonatal chronic lung diseaseK Takeda
Division of Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado 80045, USA
Anat Rec (Hoboken) 292:1045-61. 2009..These findings suggest that rosiglitazone maintains downstream PPARgamma effects and may be beneficial in the prevention of severe CLD with AHR...
- The pathology of bleomycin-induced fibrosis is associated with loss of resident lung mesenchymal stem cells that regulate effector T-cell proliferationDu Jun
Charles C Gates Center for Regenerative Medicine and Stem Cell Biology Program, University of Colorado Denver, Aurora, Colorado 80045, USA
Stem Cells 29:725-35. 2011..The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during injury...
- Physiologic and molecular consequences of endothelial Bmpr2 mutationSusan Majka
Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University, Nashville, Tennessee, USA
Respir Res 12:84. 2011..Most hereditary PAH is associated with BMPR2 mutations. However, the physiologic and molecular consequences of expression of BMPR2 mutations in PMVEC are unknown...
- Xanthine oxidase-derived ROS upregulate Egr-1 via ERK1/2 in PA smooth muscle cells; model to test impact of extracellular ROS in chronic hypoxiaTanya Hartney
Department of Pediatrics, University of Colorado Denver, Aurora, Colorado, United States of America
PLoS ONE 6:e27531. 2011..We conclude that an oxidant/antioxidant imbalance arising from loss of EC-SOD in the PA with chronic hypoxia induces Egr-1 via activation of ERK1/2 and contributes to pulmonary vascular remodeling...
- Sustained lung activity of a novel chimeric protein, SOD2/3, after intratracheal administrationMargaret B Clarke
Pediatric Critical Care, Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045, USA
Free Radic Biol Med 49:2032-9. 2010..Further testing in models of chronic lung or pulmonary vascular diseases mediated by excess superoxide should consider the longer tissue half-life of SOD2/3 as well as its potential systemic vascular effects...