Oxidative stress and reactive oxygen species signaling are now recognized to have a critical role in the pathogenesis of pulmonary hypertension (PH). The sole extracellular enzymatic defense against superoxide (O2.-) is the antioxidant extracellular superoxide dismutase (EC-SOD or SOD3). Though EC-SOD constitutes a small fraction of total SOD activity in most tissues, it is the most abundant SOD isoform in arteries. In preliminary data and the few human studies to date, EC-SOD expression and activity are decreased in end- stage PH. Loss of EC-SOD activity in animal models of PH worsens outcome, though the mechanisms are poorly understood. We hypothesize that EC-SOD localized to the pulmonary artery (PA) wall is critical to the protection against vascular inflammation and remodeling because it prevents extracellular redox-sensitive events in the matrix that can activate important signaling pathways in PA cells. We will test this hypothesis using novel mouse models, primary PASMC and macrophages, potent molecular tools and a targeted EC-SOD replacement.
Our first Aim will test the contribution of insufficient vascular EC-SOD to the development of PH;and whether its prominent vascular localization can be translated into a more effective therapeutic strategy by targeting EC-SOD replacement to the PA. We will test mouse strains with a generalized loss of EC-SOD versus a preferential loss of vascular EC-SOD, measure redox state, inflammation, pulmonary vascular remodeling and PH;and test if the effects can be reversed by targeted EC-SOD replacement.
Our second Aim will test if insufficient vascular EC-SOD, as a result of impaired scavenging of extracellular O2.-, activates TGF-?;and if this is responsible for ERK1/2 activation, Egr-1 expression and the subsequent changes in growth, inflammation and synthetic properties of PASMC.
This aim will use in vivo and in vitro models to systematically test if low vascular EC-SOD, increases O2.---dependent activation of the key growth factor, TGF-?, and if this is responsible for ERK1/2-dependent up-regulation of the transcription factor, early growth response-1, leading to changes in the growth, inflammatory, and synthetic properties of PASMC in PH. In the third Aim, we will test if low vascular EC-SOD results in oxidative fragmentation of matrix component, HA, leading to NLRP3 inflammasome activation in macrophages.
This aim will focus on a specific matrix component, hyaluronan, susceptible to superoxide-mediated fragmentation and implicated in PH.
The aim will test if insufficient vascular EC-SOD leads to oxidative fragmentation of hyaluronan and its activation of the NLRP3 inflammasome, a protein platform that processes pro-inflammatory cytokines IL-1? and IL-18 in macrophages. This proposal provides direct translational relevance by establishing the foundation to develop novel antioxidant therapies appropriately targeted to a specific vascular compartment. These findings will have important implications in a wide range of lung diseases to ultimately improve health outcome for patients with these serious problems.

Public Health Relevance

Hypoxia complicates severe lung diseases, and the development of pulmonary vascular remodeling and pulmonary hypertension in these patients leads to right heart failure, greatly increasing morbidity and mortality. Loss of a key vascular antioxidant enzyme, extracellular superoxide dismutase, promotes structural remodeling and inflammation in chronic hypoxic pulmonary hypertension. This proposal will provide the basis for the development of novel therapeutic antioxidant strategies and future human clinical trials in a range of scenarios associated with hypoxic lung diseases to improve health outcome for pediatric and adult patients with these difficult and serious problems.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL086680-07
Application #
8725721
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Xiao, Lei
Project Start
2006-12-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Fischer, Kimberly D; Hall, Sannette C; Agrawal, Devendra K (2016) Vitamin D Supplementation Reduces Induction of Epithelial-Mesenchymal Transition in Allergen Sensitized and Challenged Mice. PLoS One 11:e0149180
Hall, Sannette C; Agrawal, Devendra K (2016) Toll-like receptors, triggering receptor expressed on myeloid cells family members and receptor for advanced glycation end-products in allergic airway inflammation. Expert Rev Respir Med 10:171-84
Delaney, Cassidy; Wright, Rachel H; Tang, Jen-Ruey et al. (2015) Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension. Pediatr Res 78:634-40
Irwin, David C; Baek, Jin Hyen; Hassell, Kathryn et al. (2015) Hemoglobin-induced lung vascular oxidation, inflammation, and remodeling contribute to the progression of hypoxic pulmonary hypertension and is attenuated in rats with repeated-dose haptoglobin administration. Free Radic Biol Med 82:50-62
Acker, Shannon N; Seedorf, Gregory J; Abman, Steven H et al. (2015) Altered pulmonary artery endothelial-smooth muscle cell interactions in experimental congenital diaphragmatic hernia. Pediatr Res 77:511-9
Nozik-Grayck, Eva; Woods, Crystal; Taylor, Joann M et al. (2014) Selective depletion of vascular EC-SOD augments chronic hypoxic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 307:L868-76
Hartney, John M; Stidham, Timothy; Goldstrohm, David A et al. (2014) A common polymorphism in extracellular superoxide dismutase affects cardiopulmonary disease risk by altering protein distribution. Circ Cardiovasc Genet 7:659-66
Nahar, Kamrun; Absar, Shahriar; Gupta, Nilesh et al. (2014) Peptide-coated liposomal fasudil enhances site specific vasodilation in pulmonary arterial hypertension. Mol Pharm 11:4374-84
Villegas, Leah; Stidham, Timothy; Nozik-Grayck, Eva (2014) Oxidative Stress and Therapeutic Development in Lung Diseases. J Pulm Respir Med 4:
Marriott, Shennea; Baskir, Rubin S; Gaskill, Christa et al. (2014) ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling. Am J Physiol Cell Physiol 307:C684-98

Showing the most recent 10 out of 28 publications