Despite existing therapies, pulmonary hypertension (PH) causes significant morbidity and mortality. This proposal focuses on peroxisome proliferator-activated receptor gamma (PPARg) as a new target in PH therapy. Evolving evidence demonstrates that chronic hypoxia and other causes of PH are associated with increased expression and activity of the NADPH oxidase, Nox4. Nox4 generates reactive oxygen species that contribute to vasoconstriction, pulmonary vascular cell proliferation, and PH pathogenesis. Stimulating PPARg with thiazolidinedione ligands reduces the expression and activity of Nox4 and attenuates hypoxia-induced vascular remodeling, right ventricular hypertrophy, and pulmonary hypertension in a mouse model. Preliminary data confirm that Nox4 is upregulated in endothelial cells from patients with idiopathic pulmonary arterial hypertension. Therefore, this proposal examines the hypothesis that activation of PPARg provides a novel strategy to attenuate hypoxia-induced Nox4 expression, oxidative stress, vascular remodeling and PH. To explore this hypothesis, Aim 1 will examine the role of Nox4 in hypoxia-induced PH and its regulation by PPARg using endothelial- and smooth muscle-targeted Nox4 knockout mice.
Aim 2 will use endothelial- and smooth muscle-targeted PPARg knockout or overexpressing mice to define pulmonary vascular cell compartments that are critical for PPARg ligand-induced alterations in Nox4 and PH.
Aim 3 will examine the molecular mechanisms by which PPARg activation attenuates Nox4 expression in the pulmonary vasculature. In vitro studies will be performed using hypoxia-exposed human pulmonary artery smooth muscle or endothelial cells. The long-term goals of this proposal are to define mechanisms by which PPARg activation attenuates PH and to facilitate the development of new PH therapy.

Public Health Relevance

High blood pressure in the lung, also called pulmonary hypertension, is a devastating condition that affects many patients and for which there are no effective therapies. This proposal explores a new type of therapy for pulmonary hypertension using an animal model by examining not only the efficacy of this new treatment strategy but also the basic mechanisms by which it works. These studies have the potential to identify novel treatment strategies that could be applied to patients with pulmonary hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102167-04
Application #
8598927
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Caler, Elisabet V
Project Start
2011-01-01
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
4
Fiscal Year
2014
Total Cost
$288,551
Indirect Cost
$62,313
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yeligar, Samantha M; Kang, Bum-Yong; Bijli, Kaiser M et al. (2017) PPAR? Regulates Mitochondrial Structure and Function and HPASMC Proliferation. Am J Respir Cell Mol Biol :
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
Bedi, Brahmchetna; Yuan, Zhihong; Joo, Myungsoo et al. (2016) Enhanced Clearance of Pseudomonas aeruginosa by Peroxisome Proliferator-Activated Receptor Gamma. Infect Immun 84:1975-85
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
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
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
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
Adesina, Sherry E; Kang, Bum-Yong; Bijli, Kaiser M et al. (2015) Targeting mitochondrial reactive oxygen species to modulate hypoxia-induced pulmonary hypertension. Free Radic Biol Med 87:36-47
Kleinhenz, Jennifer M; Murphy, Tamara C; Pokutta-Paskaleva, Anastassia P et al. (2015) Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-? Disrupts Vascular Wall Structure and Function. PLoS One 10:e0139756

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