Project 3: Pulmonary Vascular-Targeted NO Therapeutic Strategies Pulmonary arterial hypertension (PAH) is a disease of the small pulmonary arteries, characterized by vasoconstriction, vascular proliferation and remodeling. The relaxation of pulmonary vascular smooth muscle cells and their abnormal proliferation is strongly modulated by nitric oxide (NO)-dependent reactions inducing both cGMP-dependent vasodilation and cGMP-independent reactions that inhibit smooth muscle proliferation and inflammatory cell function. Notably, PAH is linked with both decreased NO bioavailability and a lack of responsiveness to NO, a consequence of impaired NO biosynthesis, endothelial nitric oxide synthase (eNOS) uncoupling, dysregulated L-arginine metabolism and increased redox-dependent consumption of NO. We hypothesize that new vascular-targeted, NO-based therapeutic strategies will enhance the treatment of PAH. The research plan will evaluate the mechanisms of action of newly-appreciated signaling mediators in the context of limiting PAH. Specifically, we hypothesize that pulmonary vascular eNOS is negatively regulated by thrombospondin-l. Down-stream of eNOS, NO is then physiologically oxidized to form the potent NO signaling metabolites, nitrite and nitro-fatty acids, which dynamically regulate NO levels, p21 dependent vascular proliferation, phase 2 stress response enzymes, and peroxisome proliferator activating receptor-y signaling. The studies proposed in Project #3 will provide important new mechanistic insight and promising therapeutic strategies for modulating events central to the genesis of PAH. These goals capitalize on recent high impact discoveries related to the formation, metabolism and actions of NOderived species and synergize with central program objectives. Overall, the modulation of eNOS and NO by TSP-CD47 inhibition, nitro-fatty acid supplementation and the therapeutic application of nitrite will be evaluated in a continuum of objectives ranging from basic mechanistic studies to a highly developed translational clinical development program. This development will flow from rodent models of PAH and COPD/PAH, to clinical testing in a Pre-Clinical Core primate model of PAH and in human phase lla catheterization studies in patients with COPD and HIV associated PAH, evaluated in the Clinical Core.

Public Health Relevance

Pulmonary hypertension occurs in up to 50% of patients with advanced chronic obstructive lung disease and in 0.5-5% of patients with the acquired immunodeficiency syndrome and is associated with a dramatic increased risk of death. We propose to evaluate three novel treatment strategies targeting lung nitric oxide biology in a continuum of objectives ranging from basic mechanistic studies to a highly developed translational clinical drug development program, aimed at reversing pulmonary arterial hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
1P01HL103455-01
Application #
7982558
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Project Start
2011-06-01
Project End
2016-04-30
Budget Start
2011-06-01
Budget End
2012-04-30
Support Year
1
Fiscal Year
2011
Total Cost
$440,379
Indirect Cost
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kanias, Tamir; Sinchar, Derek; Osei-Hwedieh, David et al. (2016) Testosterone-dependent sex differences in red blood cell hemolysis in storage, stress, and disease. Transfusion 56:2571-2583
Procter, Nathan Ek; Ball, Jocasta; Ngo, Doan Tm et al. (2016) Gender and tachycardia: independent modulation of platelet reactivity in patients with atrial fibrillation. J Geriatr Cardiol 13:202-8
Vanderpool, Rebecca R; Rischard, Franz; Naeije, Robert et al. (2016) Simple functional imaging of the right ventricle in pulmonary hypertension: Can right ventricular ejection fraction be improved? Int J Cardiol 223:93-94
Maron, Bradley A; Gladwin, Mark T; Simon, Marc A (2016) Update in Pulmonary Vascular Disease 2015. Am J Respir Crit Care Med 193:1337-44
Gladwin, Mark T (2016) Cardiovascular complications and risk of death in sickle-cell disease. Lancet 387:2565-74
Ambrozova, Gabriela; Martiskova, Hana; Koudelka, Adolf et al. (2016) Nitro-oleic acid modulates classical and regulatory activation of macrophages and their involvement in pro-fibrotic responses. Free Radic Biol Med 90:252-60
Al Ghouleh, Imad; Meijles, Daniel N; Mutchler, Stephanie et al. (2016) Binding of EBP50 to Nox organizing subunit p47phox is pivotal to cellular reactive species generation and altered vascular phenotype. Proc Natl Acad Sci U S A 113:E5308-17
Azarov, Ivan; Wang, Ling; Rose, Jason J et al. (2016) Five-coordinate H64Q neuroglobin as a ligand-trap antidote for carbon monoxide poisoning. Sci Transl Med 8:368ra173
Meijles, Daniel N; Pagano, Patrick J (2016) Nox and Inflammation in the Vascular Adventitia. Hypertension 67:14-9
Ambrozova, Gabriela; Fidlerova, Tana; Verescakova, Hana et al. (2016) Nitro-oleic acid inhibits vascular endothelial inflammatory responses and the endothelial-mesenchymal transition. Biochim Biophys Acta 1860:2428-37

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