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
Kim-Campbell, Nahmah; Gretchen, Catherine; Callaway, Clifton et al. (2017) Cell-Free Plasma Hemoglobin and Male Gender Are Risk Factors for Acute Kidney Injury in Low Risk Children Undergoing Cardiopulmonary Bypass. Crit Care Med 45:e1123-e1130
Meng, Qingqing; Lai, Yen-Chun; Kelly, Neil J et al. (2017) Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction. Am J Respir Cell Mol Biol 56:497-505
Meijles, Daniel N; Sahoo, Sanghamitra; Al Ghouleh, Imad et al. (2017) The matricellular protein TSP1 promotes human and mouse endothelial cell senescence through CD47 and Nox1. Sci Signal 10:
Hughan, Kara S; Wendell, Stacy Gelhaus; Delmastro-Greenwood, Meghan et al. (2017) Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate. Hypertension :
Gladwin, Mark T (2017) Translational Advances in the Field of Pulmonary Hypertension Bench to Bedside: How Fundamental Discoveries in Science Are Advancing Our Understanding and Therapy of Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 195:1-3
Fazzari, Marco; Khoo, Nicholas K H; Woodcock, Steven R et al. (2017) Nitro-fatty acid pharmacokinetics in the adipose tissue compartment. J Lipid Res 58:375-385
Grzegorzewska, Agnieszka P; Seta, Francesca; Han, Rong et al. (2017) Dimethyl Fumarate ameliorates pulmonary arterial hypertension and lung fibrosis by targeting multiple pathways. Sci Rep 7:41605
Kelly, Neil J; Radder, Josiah E; Baust, Jeffrey J et al. (2017) Mouse Genome-Wide Association Study of Preclinical Group II Pulmonary Hypertension Identifies Epidermal Growth Factor Receptor. Am J Respir Cell Mol Biol 56:488-496
Radder, Josiah E; Zhang, Yingze; Gregory, Alyssa D et al. (2017) Extreme Trait Whole-Genome Sequencing Identifies PTPRO as a Novel Candidate Gene in Emphysema with Severe Airflow Obstruction. Am J Respir Crit Care Med 196:159-171
Pena, Andressa; Kobir, Ahasanul; Goncharov, Dmitry et al. (2017) Pharmacological Inhibition of mTOR Kinase Reverses Right Ventricle Remodeling and Improves Right Ventricle Structure and Function in Rats. Am J Respir Cell Mol Biol 57:615-625

Showing the most recent 10 out of 162 publications