Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling

Gong, Kaizheng; Xing, Dong; Li, Peng; Aksut, Baran; Ambalavanan, Namasivayam; Yang, Qinglin; Nozell, Susan E.; Oparil, Suzanne; Chen, Yiu-Fai

doi:10.1152/ajplung.00062.2011

Cited by 55 publications

(51 citation statements)

References 34 publications

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“…In the pulmonary vasculature, RG treatment was shown to attenuate pulmonary arterial hypertension and vascular remodeling in chronic-hypoxia mouse models. Mechanisms include alterations in NADPH subunit expression, superoxide levels, regulation of Nox4 expression through NF-kappaB, and a down regulation of PPARγ through transforming growth factor-beta (15)(16)(17). Thus, the findings of the present study are consistent with this emerging literature, but are unique in demonstrating a role for PPARγ in early selective pulmonary vascular endothelial dysfunction secondary to increased pulmonary blood flow.…”

Section: Discussionsupporting

confidence: 86%

Erratum: Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

Oishi¹,

Sharma

Datar³

et al. 2013

Pediatr Res

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Section: Discussionsupporting

confidence: 86%

Erratum: Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

Oishi¹,

Sharma

Datar³

et al. 2013

Pediatr Res

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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

134

147

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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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“…Peroxisome proliferator-activated receptor (PPAR) g belongs to a kind of ligand-activated nuclear hormone receptor superfamily, which is ubiquitously expressed in pulmonary vascular endothelial and smooth muscle cells, and acts as a transcription factor to modulate the transcription of a number of genes (8). Previous studies reported that PPARg is down-regulated in the lungs (9,10) and distal PAs (11) of experimental PH models, whereas restoration of PPARg by specific agonists can markedly attenuate the PH pathogenesis by normalizing the elevated right ventricle systolic pressure and distal PA remodeling (12)(13)(14). Moreover, we further demonstrated the molecular mechanisms that PPARg inhibits PA remodeling and PASMC proliferation, mainly by targeting SOCE and TRPC proteins (11,13).…”

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confidence: 99%

Peroxisome Proliferator–Activated Receptor γ–Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1–Dependent Mechanism

Yang

Qian

et al. 2015

Am J Respir Cell Mol Biol

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Our previous publication demonstrated that peroxisome proliferator-activated receptor g (PPARg) inhibits the pathogenesis of chronic hypoxia (CH)-induced pulmonary hypertension by targeting store-operated calcium entry (SOCE) in rat distal pulmonary arterial smooth muscle cells (PASMCs). In this study, we aim to determine the role of a membrane scaffolding protein, caveolin-1, during the suppressive process of PPARg on SOCE. Adult (6-8 weeks) male Wistar rats (200-250 g) were exposed to CH (10% O 2 ) for 21 days to establish CH-induced pulmonary hypertension. Primary cultured rat distal PASMCs were applied for the molecular biological experiments. First, hypoxic exposure led to 2.5-fold and 1-fold increases of caveolin-1 protein expression in the distal pulmonary arteries and PASMCs, respectively. Second, effective knockdown of caveolin-1 significantly reduced hypoxia-induced SOCE for 58.2% and 41.5%, measured by Mn 21 quenching and extracellular Ca 21 restoration experiments, respectively. These results suggested that caveolin-1 acts as a crucial regulator of SOCE, and hypoxia-up-regulated caveolin-1 largely accounts for hypoxia-elevated SOCE in PASMCs. Then, by using a high-potency PPARg agonist, GW1929, we detected that PPARg activation inhibited SOCE and caveolin-1 protein for 62.5% and 59.8% under hypoxia, respectively, suggesting that caveolin-1 also acts as a key target during the suppressive process of PPARg on SOCE in PASMCs. Moreover, by using effective small interfering RNAs against PPARg and caveolin-1, and PPARg antagonist, T0070907, we observed that PPARg plays an inhibitory role on caveolin-1 protein by promoting its lysosomal degradation, without affecting the messenger RNA level. PPARg inhibits SOCE, at least partially, by suppressing cellular caveolin-1 protein in PASMCs.Keywords: pulmonary hypertension; peroxisome proliferator-activated receptor g; caveolin-1; store-operated calcium entry; pulmonary arterial smooth muscle cells Pulmonary hypertension (PH) is a severe pulmonary vascular disease characterized by sustained increase in the pulmonary arterial pressure and excessive thickening and remodeling of the distal small pulmonary arteries (PAs). These functional and structural changes then lead to right ventricular hypertrophy and, eventually, heart failure. Nowadays, it is well accepted that the dysregulation of the proliferation and migration of the PA smooth muscle cells (PASMCs) are the main reasons contributing to the abnormally excessive thickening and remodeling of the distal PAs during PH pathogenesis (1-3).Previous studies have described that the increase of the intracellular free calcium concentration ([Ca 21 ] i ) acts a major factor

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Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling

Cited by 55 publications

References 34 publications

Erratum: Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

Erratum: Rosiglitazone preserves pulmonary vascular function in lambs with increased pulmonary blood flow

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

Peroxisome Proliferator–Activated Receptor γ–Mediated Inhibition on Hypoxia-Triggered Store-Operated Calcium Entry. A Caveolin-1–Dependent Mechanism

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