Pulmonary hypertension (PH) is a complex disorder that causes significant morbidity and mortality. Mounting evidence suggests that metabolic derangements account for the pathophysiology underlying PH. This proposal focuses peroxisome proliferator-activated receptor gamma (PPAR?), a major metabolic regulator that is decreased PH. Hypoxia and other causes of PH decrease PPAR? expression which increases NADPH oxidase 4 (Nox4) expression and activity. Nox4 generates reactive oxygen species (ROS) that contribute to pulmonary vascular cell proliferation and PH pathogenesis. On the other hand, stimulating PPAR? reduces the expression and activity of Nox4 and attenuates hypoxia-induced vascular remodeling, right ventricular hypertrophy, and PH. The mechanisms by which PPAR? modulates PH continue to be defined. Preliminary data suggest that reductions in PPAR? reduce the expression of PPAR? coactivator 1 alpha (PGC1?) and uncoupling protein 2 (UCP2), proteins that regulate mitochondrial (MT) biogenesis and reactive oxygen species (ROS) generation, respectively. The proposed studies will test the hypothesis that PPAR? depletion reduces pulmonary artery smooth muscle cell (PASMC) PGC1? and UCP2 and stimulates MT dysfunction and ROS production. The investigators further postulate that MT ROS activate the ERK 1/2-NF-?B axis to increase Nox4 expression and H2O2 generation which promote PASMC proliferation, pulmonary vascular remodeling, and PH. To test this hypothesis, Specific Aim 1 will explore the role of reduced PPAR? activity in MT dysfunction, Nox4 induction, and PASMC proliferation using complementary in vitro and in vivo models. Genetic or pharmacological reductions in PPAR? activity will be used in human PASMC in vitro, and inducible, smooth muscle-targeted PPAR? knockout mice (smPPAR?KO) will be employed in vivo.
Specific Aim 2 will examine the role of reductions in PPAR? in hypoxia-induced alterations in PGC1? and UCP2, MT dysfunction, Nox4 induction, and PASMC proliferation. In vitro and in vivo gain and loss of PPAR? function models will be exposed to well characterized control or hypoxic conditions, and MT function, ROS production, and PASMC proliferation will be determined. Hypoxia-induced PH will be assessed with measures of right ventricular systolic pressure, right ventricular hypertrophy, and ventricular function (echocardiography). PASMC proliferation will be examined with immunohistochemistry for proliferating cellular nuclear antigen and morphometric analysis of lung sections stained for ?-smooth muscle actin. The ability of full and partial (10- nitro-oleic acid) PPAR? ligands to attenuate hypoxic proliferatin and PH will be tested. Critical observations will be confirmed in PASMC isolated from patients with idiopathic pulmonary arterial hypertension. The proposed studies, conducted by a productive and collaborative research team, will advance understanding of the role of PPAR? in regulating PASMC phenotype during health and disease and identify novel strategies by which targeting PPAR? can interrupt PH pathogenesis.

Public Health Relevance

The pathogenesis of pulmonary hypertension (PH) is incompletely understood, and despite existing therapies, this disorder continues to cause significant morbidity and mortality. This proposal focuses on the peroxisome proliferator-activated receptor-gamma within cells of the lung vasculature and how reductions in this receptor contribute to the pathology of PH. The successful completion of the proposed studies has the potential to identify novel therapeutic targets to reduce PH morbidity and mortality.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102167-08
Application #
9485981
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2011-01-01
Project End
2019-05-31
Budget Start
2018-06-01
Budget End
2019-05-31
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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Bedi, Brahmchetna; Maurice, Nicholas M; Ciavatta, Vincent T et al. (2017) Peroxisome proliferator-activated receptor-? agonists attenuate biofilm formation by Pseudomonas aeruginosa. FASEB J 31:3608-3621
Green, David E; Murphy, Tamara C; Kang, Bum-Yong et al. (2017) Peroxisome proliferator-activated receptor-? enhances human pulmonary artery smooth muscle cell apoptosis through microRNA-21 and programmed cell death 4. Am J Physiol Lung Cell Mol Physiol 313:L371-L383
Kang, Bum-Yong; Park, Kathy; Kleinhenz, Jennifer M et al. (2017) Peroxisome Proliferator-Activated Receptor ? Regulates the V-Ets Avian Erythroblastosis Virus E26 Oncogene Homolog 1/microRNA-27a Axis to Reduce Endothelin-1 and Endothelial Dysfunction in the Sickle Cell Mouse Lung. Am J Respir Cell Mol Biol 56:131-144
Adesina, Sherry E; Wade, Brandy E; Bijli, Kaiser M et al. (2017) Hypoxia inhibits expression and function of mitochondrial thioredoxin 2 to promote pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 312:L599-L608
Yeligar, Samantha M; Mehta, Ashish J; Harris, Frank L et al. (2016) Peroxisome Proliferator-Activated Receptor ? Regulates Chronic Alcohol-Induced Alveolar Macrophage Dysfunction. Am J Respir Cell Mol Biol 55:35-46
Blum, Justine I; Bijli, Kaiser M; Murphy, Tamara C et al. (2016) Time-dependent PPAR? Modulation of HIF-1? Signaling in Hypoxic Pulmonary Artery Smooth Muscle Cells. Am J Med Sci 352:71-9
Bijli, Kaiser M; Kang, Bum-Yong; Sutliff, Roy L et al. (2016) Proline-rich tyrosine kinase 2 downregulates peroxisome proliferator-activated receptor gamma to promote hypoxia-induced pulmonary artery smooth muscle cell proliferation. Pulm Circ 6:202-10
Kang, Bum-Yong; Park, Kathy K; Kleinhenz, Jennifer M et al. (2016) Peroxisome Proliferator-Activated Receptor ? and microRNA 98 in Hypoxia-Induced Endothelin-1 Signaling. Am J Respir Cell Mol Biol 54:136-46
Bedi, Brahmchetna; Yuan, Zhihong; Joo, Myungsoo et al. (2016) Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma. Infect Immun 84:1975-1985

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