Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone

Nicola, Teodora; Ambalavanan, Namasivayam; Zhang, Wei; James, Masheika L.; Rehan, Virender K.; Halloran, Brian; Olave, Nelida; Bulger, Arlene; Oparil, Suzanne; Chen, Yiu-Fai

doi:10.1152/ajplung.00074.2011

Cited by 50 publications

(62 citation statements)

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“…First, Awonusonu and colleagues found that not all lipofibroblasts are Thy-1 (1) (38). Second, whereas the earlier-appearing lipofibroblast population was shown to be important in surfactant production in vitro (40, 41), Thy-1 2/2 mouse pups do not exhibit respiratory distress or lung histology consistent with surfactant deficiency (10,25,42). The prevention of lipofibroblast-to-myofibroblast differentiation by the prenatal administration of rosiglitazone increased the numbers of lamellar bodies in alveolar Type II cells in rats on PND1 (43), supporting the assertion that earlier-appearing lipofibroblasts may play a role in surfactant production, but the later-appearing Thy-1 (1) lipofibroblasts do ;not.…”

Section: Discussionmentioning

confidence: 99%

“…Hyperoxia, hypoxia, and nicotine exposure stimulate lipofibroblasts to myofibroblast differentiation and impair alveolar development (9)(10)(11)(12). Peroxisome proliferator-activated receptor-g (PPARg) signaling is important in lipofibroblast differentiation (13,14), and PPARg agonists can reverse lipofibroblast to myofibroblast differentiation and restore alveolar development in murine and rat models (10,15).…”

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Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

Varisco

Ambalavanan

Whitsett

et al. 2012

Am J Respir Cell Mol Biol

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Thy-1 is a glycosylphosphytidylinositol-linked cell-surface glycoprotein present on a subset of lung fibroblasts, which plays an important role in postnatal alveolarization. In the present study, we define the role of Thy-1 in pulmonary lipofibroblast differentiation and in the regulation of lipid homeostasis via peroxisome proliferator-activated receptor-g (PPARg). Thy-1 was associated with interstitial cells containing lipid droplets in vivo. The transfection of Thy-1 into Thy-1 (2) fibroblasts increased triglyceride content, fatty-acid uptake, and the expression of the lipofibroblast marker adipocyte differentiationrelated protein. Thy-1 (1) fibroblasts exhibited 2.4-fold higher PPARg activity, and the inhibition or activation of PPARg reduced and increased triglyceride content, respectively. Thy-1 (2) fibroblasts were not responsive to either of the PPARg agonists ciglitazone or prostaglandin J 2 , supporting the importance of Thy-1 in signaling via PPARg. Thy-1 (1) fibroblasts expressed significantly higher concentrations of fatty-acid transporter protein-3 mRNA, and demonstrated higher rates of fatty-acid uptake and increased triglyceride content. The inhibition of fatty-acid transporter protein function reduced Thy-1 (1) fibroblast lipid content. The expression of Thy-1 in C57BL/6 lung fibroblasts increased during the neonatal period, coinciding with the onset of alveolarization. Thy-1 promoted lipofibroblast differentiation via the expression of PPARg, stimulated lipid accumulation via fatty-acid esterification, and enhanced the fatty-acid uptake mediated by fattyacid transporter proteins. Thy-1 is important in the regulation of lipofibroblast differentiation in the developing lung.Keywords: Thy-1; lipofibroblast; PPARg; lipid metabolismBeginning at 35 weeks after conception and continuing for up to 8 years after birth, the alveolar stage of lung development is marked by the sequential division of larger airspaces into smaller ones by secondary alveolar septa (1, 2). From term birth until adulthood, the 5-fold increase in the number of alveoli and the 20-fold increase in alveolar surface area are critical in meeting the increasing oxygenation and ventilation needs of human growth and activity (2, 3). Premature birth, exposure to high concentrations of inspired oxygen, and mechanical ventilation lead to impaired alveolar development and chronic lung disease (4). The impaired lung function of chronic lung disease results in significant morbidity, mortality, and healthcare costs from early life through adulthood (5-8). Understanding how the different tissues of the lung behave during normal and impaired alveolar development is a key first step toward restoring alveolarization and attenuating the burden of respiratory disease after premature birth.Pulmonary lipofibroblasts comprise an incompletely characterized population of lipid-containing interstitial cells that play an important role in alveolarization. Hyperoxia, hypoxia, and nicotine exposure stimulate lipofibroblasts to myofibroblast differentiation a...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

Varisco

Ambalavanan

Whitsett

et al. 2012

Am J Respir Cell Mol Biol

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“…Administration of GKT137831 or rosiglitazone attenuated hypoxic reductions in lung PPARg expression ( Figure 7A). Transforming growth factor (TGF)-b1 contributes to hypoxiamediated Nox4 expression and activity and HPASMC proliferation (24,(28)(29)(30), and PPARg ligands have been shown to modulate TGF-b1 signaling in the lung (31)(32)(33). We therefore examined the impact of Nox4 inhibition with GKT137831 on hypoxia-induced TGF-b1 expression in the lung.…”

Section: Administration Of Gkt137831 or Rosiglitazone Attenuates Hypomentioning

confidence: 99%

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

Green

Murphy

Kang

et al. 2012

Am J Respir Cell Mol Biol

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Increased NADP reduced (NADPH) oxidase 4 (Nox4) and reduced expression of the nuclear hormone receptor peroxisome proliferator-activated receptor g (PPARg) contribute to hypoxiainduced pulmonary hypertension (PH). To examine the role of Nox4 activity in pulmonary vascular cell proliferation and PH, the current study used a novel Nox4 inhibitor, GKT137831, in hypoxiaexposed human pulmonary artery endothelial or smooth muscle cells (HPAECs or HPASMCs) in vitro and in hypoxia-treated mice in vivo. HPAECs or HPASMCs were exposed to normoxia or hypoxia (1% O 2 ) for 72 hours with or without GKT137831. Cell proliferation and Nox4, PPARg, and transforming growth factor (TGF)b1 expression were measured. C57Bl/6 mice were exposed to normoxia or hypoxia (10% O 2 ) for 3 weeks with or without GKT137831 treatment during the final 10 days of exposure. Lung PPARg and TGF-b1 expression, right ventricular hypertrophy (RVH), right ventricular systolic pressure (RVSP), and pulmonary vascular remodeling were measured. GKT137831 attenuated hypoxia-induced H 2 O 2 release, proliferation, and TGF-b1 expression and blunted reductions in PPARg in HPAECs and HPASMCs in vitro. In vivo GKT137831 inhibited hypoxia-induced increases in TGF-b1 and reductions in PPARg expression and attenuated RVH and pulmonary artery wall thickness but not increases in RVSP or muscularization of small arterioles. This study shows that Nox4 plays a critical role in modulating proliferative responses of pulmonary vascular wall cells. Targeting Nox4 with GKT137831 provides a novel strategy to attenuate hypoxiainduced alterations in pulmonary vascular wall cells that contribute to vascular remodeling and RVH, key features involved in PH pathogenesis.Keywords: rosiglitazone; PPARg; TGF-b; pulmonary hypertension Pulmonary hypertension (PH) is a progressive disorder associated with significant morbidity and mortality. Although recent therapeutic advances have improved survival for patients with PH, the prognosis remains poor (1). The pathobiology of PH is complex, and factors that contribute to endothelial dysfunction have been implicated in pathogenesis (2, 3). Among these factors, NADP reduced (NADPH) oxidase enzymes that produce reactive oxygen species (ROS) contribute to the development of a variety of vascular diseases, such as atherosclerosis (4) and systemic (5) and pulmonary hypertension (6). NADPH oxidases catalyze the reduction of molecular oxygen to generate superoxide (O 2 .2 ), hydrogen peroxide (H 2 O 2 ), or secondary oxidants (7). Seven isoforms of the catalytic moiety of the nonphagocytic NADPH oxidase enzyme have been described (Nox1-5, Duox1-2). These subunits are homologous to the catalytic moiety of the prototype phagocytic NADPH oxidase Nox2 (or gp91 phox ) but differ from each other regarding cellular localization, tissue distribution, regulation, activation, and expression (7,8). For example, although both Nox1 and Nox4 are expressed in vascular smooth muscle cells (VSMCs), they are targeted to discreet intracellular locations, are differe...

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“…Multiple research works have demonstrated that PPARγ has broad protective effects on the cardiovascular system in addition to the regulation of adipogenesis and glucose metabolism. [3][4][5][6] Activation of PPARγ provides beneficial effects in anti-inflammation and anti-apoptosis, suggesting that activation of PPARγ may be vital in a variety of diseases. [7][8][9] Accumulating evidence demonstrated that activation of PPARγ may be a novel PAH therapeutic target.…”

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PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

Xü

Liu

et al. 2017

Int. Heart J.

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SummaryPulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling leading to right ventricular hypertrophy (RVH) and failure. Peroxisome proliferator-activated receptor γ (PPARγ), a member of nuclear receptors, has been proved to ameliorate PAH. However, its effect on PAH-induced right ventricular failure (RVF) remains unknown. Therefore, we investigated the therapeutic potential of PPARγ in preventing monocrotaline (MCT)-induced RV dysfunction. The PAH model was induced by MCT administration. Male rats were administered with MCT to develop PAH and RVF formed by approximately day 30. Significant increase in RV area, RVAW resulted in an ascending RV index. However, the LV function including EF, FS, and LVID did not change significantly. PPARγ agonist prevented PAH-induced RVF by preserving RV index and preventing RVH. PPARγ's beneficial effects seem to result from various factors, including anti-apoptosis, preservation RV index, reversal of inflammation, improvement of glucolipid metabolism, reduction of ROS. In a word, PPARγ agonist prevents the development of RVF.( Int Heart J 2017; 58: 948-956)

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Hypoxia-induced inhibition of lung development is attenuated by the peroxisome proliferator-activated receptor-γ agonist rosiglitazone

Cited by 50 publications

References 35 publications

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

Thy-1 Signals through PPARγ to Promote Lipofibroblast Differentiation in the Developing Lung

The Nox4 Inhibitor GKT137831 Attenuates Hypoxia-Induced Pulmonary Vascular Cell Proliferation

PPARγ Alleviates Right Ventricular Failure Secondary to Pulmonary Arterial Hypertension in Rats

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