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 #
5R01HL102167-03
Application #
8402582
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
2013-01-01
Budget End
2013-12-31
Support Year
3
Fiscal Year
2013
Total Cost
$305,288
Indirect Cost
$66,016
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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Sutliff, Roy L; Hilenski, Lula L; Amanso, Angelica M et al. (2013) Polymerase delta interacting protein 2 sustains vascular structure and function. Arterioscler Thromb Vasc Biol 33:2154-61
Lu, Xianghuai; Bijli, Kaiser M; Ramirez, Allan et al. (2013) Hypoxia downregulates PPARýý via an ERK1/2-NF-*B-Nox4-dependent mechanism in human pulmonary artery smooth muscle cells. Free Radic Biol Med 63:151-60
Kang, Bum-Yong; Kleinhenz, Jennifer M; Murphy, Tamara C et al. (2011) The PPAR? ligand rosiglitazone attenuates hypoxia-induced endothelin signaling in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 301:L881-91