To address our overall hypotheses that Pulmonary vascular disease/pulmonary hypertension (PHTN) is an important component of the COPD syndrome with distinct genetic and environmental determinants, we will 1. Identify genes responsible for cigarette smoke related PHTN using a mouse model and by exposing 36 strains of mice to long-term cigarette smoke and quantifying the PHTN phenotype in each strain. Given the dense SNP map, we will perform in silico mapping to identify specific genes responsible for the phenotype. We will also perform classic QTL crosses and use bioinformatics to identify the genes. 2. We have identified high fat diet as an important environmental factor that we hypothesize aggravates cigarette smoke related PHTN. We hypothesize that the mechanism for this synergistic effect of high fat is that both high fat and smoke cause ER stress and endothelial dysfunction, interfering with NO production. Low NO + the saturated fat excess will interfere with NO-mediated nitration of the polyunsaturated fatty acid, linoleic acid (LN02), highest affinity endogenous PPARy agonist known. Impaired PPARy signaling then leads to vascular PDGF-mediated smooth muscle cell proliferation and PHTN. We will both dissect this pathway and treat mice with exogenous PPARy agonists, thiazolidinedioines (TZDs). 3. To prepare for translation in years 6- 10 we will assess vascular disease by chest CT scans in a cohort of well-characterized patients with a spectrum of airflow obstruction and emphysema. We will derive and correlate indices of pulmonary vascular disease with physiology, patient symptoms, exercise performance and biomarkers of vascular disease. In addition to anatomic parameters, CT scan data will be used in conjunction with computational fluid dynamic tools to create personalized functional models of the pulmonary circulation. With the Clinical Core, we will also recruit a cohort of patients with COPD who will undergo right heart catheterizations (along with PFTs, echocardiography, exercise testing and chest CT) both to validate our findings and to test the hypothesis that vascular characteristics extracted from chest CT scan will correlate with pulmonary hypertension and pulmonary vascular responsiveness.

Public Health Relevance

In this project we will assess the overall hypotheses that 1. Pulmonary vascular disease/pulmonary hypertension (PHTN) is an important component of the COPD syndrome that has distinct genetic and environmental determinants and has an independent effect on symptoms and natural history, and 2. Molecular mechanisms identified in mice, are relevant to humans, and there are overiapping mechanisms involved in primary and secondary pulmonary hypertension, including COPD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL103455-03
Application #
8469898
Study Section
Special Emphasis Panel (ZHL1-CSR-A)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$578,957
Indirect Cost
$196,808
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Snyder, Nathaniel W; Golin-Bisello, Franca; Gao, Yang et al. (2015) 15-Oxoeicosatetraenoic acid is a 15-hydroxyprostaglandin dehydrogenase-derived electrophilic mediator of inflammatory signaling pathways. Chem Biol Interact 234:144-53
Simon, Marc A; Lacomis, Christopher D; George, M Patricia et al. (2014) Isolated right ventricular dysfunction in patients with human immunodeficiency virus. J Card Fail 20:414-21
Hill, Michael R; Simon, Marc A; Valdez-Jasso, Daniela et al. (2014) Structural and mechanical adaptations of right ventricle free wall myocardium to pressure overload. Ann Biomed Eng 42:2451-65
Lai, Yen-Chun; Potoka, Karin C; Champion, Hunter C et al. (2014) Pulmonary arterial hypertension: the clinical syndrome. Circ Res 115:115-30
Griffin, Paula J; Sebastiani, Paola; Edward, Heather et al. (2014) The genetics of hemoglobin A2 regulation in sickle cell anemia. Am J Hematol 89:1019-23
Frazziano, Giovanna; Al Ghouleh, Imad; Baust, Jeff et al. (2014) Nox-derived ROS are acutely activated in pressure overload pulmonary hypertension: indications for a seminal role for mitochondrial Nox4. Am J Physiol Heart Circ Physiol 306:H197-205
Klinke, Anna; Möller, Annika; Pekarova, Michaela et al. (2014) Protective effects of 10-nitro-oleic acid in a hypoxia-induced murine model of pulmonary hypertension. Am J Respir Cell Mol Biol 51:155-62
Sharifi-Sanjani, Maryam; Shoushtari, Ali Hakim; Quiroz, Marisol et al. (2014) Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3. J Am Heart Assoc 3:e000670
Fazzari, Marco; Trostchansky, Andrés; Schopfer, Francisco J et al. (2014) Olives and olive oil are sources of electrophilic fatty acid nitroalkenes. PLoS One 9:e84884
Zemke, Anna C; Shiva, Sruti; Burns, Jane L et al. (2014) Nitrite modulates bacterial antibiotic susceptibility and biofilm formation in association with airway epithelial cells. Free Radic Biol Med 77:307-16

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