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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Respiratory Integrative Biology and Translational Research Study Section (RIBT)
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Caler, Elisabet V
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Emory University
Internal Medicine/Medicine
Schools of Medicine
United States
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Kang, Bum-Yong; Park, Kathy K; Kleinhenz, Jennifer M et al. (2016) Peroxisome Proliferator-Activated Receptor γ and microRNA 98 in Hypoxia-Induced Endothelin-1 Signaling. Am J Respir Cell Mol Biol 54:136-46
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
Green, David E; Murphy, Tamara C; Kang, Bum-Yong et al. (2015) PPARγ Ligands Attenuate Hypoxia-Induced Proliferation in Human Pulmonary Artery Smooth Muscle Cells through Modulation of MicroRNA-21. PLoS One 10:e0133391
Kleinhenz, Jennifer M; Murphy, Tamara C; Pokutta-Paskaleva, Anastassia P et al. (2015) Smooth Muscle-Targeted Overexpression of Peroxisome Proliferator Activated Receptor-γ Disrupts Vascular Wall Structure and Function. PLoS One 10:e0139756
Bijli, Kaiser M; Kleinhenz, Jennifer M; Murphy, Tamara C et al. (2015) Peroxisome proliferator-activated receptor gamma depletion stimulates Nox4 expression and human pulmonary artery smooth muscle cell proliferation. Free Radic Biol Med 80:111-20
Yeligar, Samantha M; Harris, Frank L; Hart, C Michael et al. (2014) Glutathione attenuates ethanol-induced alveolar macrophage oxidative stress and dysfunction by downregulating NADPH oxidases. Am J Physiol Lung Cell Mol Physiol 306:L429-41
Porter, Kristi M; Kang, Bum-Yong; Adesina, Sherry E et al. (2014) Chronic hypoxia promotes pulmonary artery endothelial cell proliferation through H2O2-induced 5-lipoxygenase. PLoS One 9:e98532
Wongtrakool, Cherry; Grooms, Kora; Bijli, Kaiser M et al. (2014) Nicotine stimulates nerve growth factor in lung fibroblasts through an NFκB-dependent mechanism. PLoS One 9:e109602
Kang, Bum-Yong; Park, Kathy K; Green, David E et al. (2013) Hypoxia mediates mutual repression between microRNA-27a and PPARγ in the pulmonary vasculature. PLoS One 8:e79503
Sutliff, Roy L; Hilenski, Lula L; Amanso, Angélica M et al. (2013) Polymerase delta interacting protein 2 sustains vascular structure and function. Arterioscler Thromb Vasc Biol 33:2154-61

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