Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling
Hypoxia induces downregulation of PPAR-γ in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-β signaling
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DOI：
10.1152/ajplung.00062.2011
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发表时间：
2011-12-01
影响因子：
4.9
通讯作者：
Chen, Yiu-Fai
中科院分区：
文献类型：
--
作者：
Gong, Kaizheng;Xing, Dongqi;Chen, Yiu-Fai
龚K，邢D，李P，Aksut B，Ambalavanan N，Yang Q，Nozell SE，Oparil S，Chen Y-F.缺氧通过转化生长因子-β信号转导诱导离体肺动脉平滑肌细胞和大鼠肺中PPAR-gamma的下调。美国生理学杂志肺细胞分子生理学301：L 899-L907，2011年。首次发表于2011年9月16日; doi：10.1152/ajplung.00062.2011.-慢性缺氧激活转化生长因子-β（TGF-β）信号传导并导致肺血管重构。过氧化物酶体增殖物激活受体-γ（PPAR-gamma）的药理学激活已显示在啮齿动物模型中预防缺氧诱导的肺动脉高压和血管重塑，表明PPAR-gamma在慢性缺氧应激下的血管保护作用。本研究在低氧应激条件下，对肺动脉小肌细胞（PASMCs）TGF-β/Smad信号通路与PPAR-gamma之间的功能相互作用进行了验证。我们观察到，慢性缺氧导致整个肺匀浆（大鼠和小鼠）和肥大的肺动脉和分离的PASMCs中的PPAR-gamma蛋白表达显著降低。使用一个转基因小鼠模型与诱导型TGF-β受体II型显性负突变的过度表达，我们证明了TGF-β途径的中断显着衰减慢性缺氧诱导的肺中PPAR-gamma的下调。类似地，在分离的大鼠PASMCs中，用TGF-β的中和抗体或选择性TGF-β受体I型抑制剂SB 431542拮抗TGF-β信号传导有效地减弱了缺氧诱导的PPAR-gamma下调。此外，我们已经证明，TGF-β 1治疗抑制在常氧条件下PASMCs的PPAR-gamma表达。染色质免疫沉淀分析显示，TGF-β 1处理显著增加了PASMCs中Smad 2/3、Smad 4和转录辅阻遏物组蛋白去乙酰化酶1与PPAR-gamma启动子的结合。相反，用PPAR-gamma激动剂罗格列酮治疗减弱了PASMCs中TGF-β 1诱导的细胞外基质分子表达和生长因子。这些数据提供了强有力的证据表明，TGF-β/Smad信号的激活，通过转录抑制PAR-γ表达，介导慢性缺氧诱导的肺中PPAR-γ表达下调。
Gong K, Xing D, Li P, Aksut B, Ambalavanan N, Yang Q, Nozell SE, Oparil S, Chen Y-F. Hypoxia induces downregulation of PPAR-gamma in isolated pulmonary arterial smooth muscle cells and in rat lung via transforming growth factor-beta signaling. Am J Physiol Lung Cell Mol Physiol 301: L899-L907, 2011. First published September 16, 2011; doi: 10.1152/ajplung.00062.2011.-Chronic hypoxia activates transforming growth factor-beta (TGF-beta) signaling and leads to pulmonary vascular remodeling. Pharmacological activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has been shown to prevent hypoxia-induced pulmonary hypertension and vascular remodeling in rodent models, suggesting a vasoprotective effect of PPAR-gamma under chronic hypoxic stress. This study tested the hypothesis that there is a functional interaction between TGF-beta/Smad signaling pathway and PPAR-gamma in isolated pulmonary artery small muscle cells (PASMCs) under hypoxic stress. We observed that chronic hypoxia led to a dramatic decrease of PPAR-gamma protein expression in whole lung homogenates (rat and mouse) and hypertrophied pulmonary arteries and isolated PASMCs. Using a transgenic model of mouse with inducible overexpression of a dominant-negative mutant of TGF-beta receptor type II, we demonstrated that disruption of TGF-beta pathway significantly attenuated chronic hypoxia-induced downregulation of PPAR-gamma in lung. Similarly, in isolated rat PASMCs, antagonism of TGF-beta signaling with either a neutralizing antibody to TGF-beta or the selective TGF-beta receptor type I inhibitor SB431542 effectively attenuated hypoxia-induced PPAR-gamma downregulation. Furthermore, we have demonstrated that TGF-beta 1 treatment suppressed PPAR-gamma expression in PASMCs under normoxia condition. Chromatin immunoprecipitation analysis showed that TGF-beta 1 treatment significantly increased binding of Smad2/3, Smad4, and the transcriptional corepressor histone deacetylase 1 to the PPAR-gamma promoter in PASMCs. Conversely, treatment with the PPAR-gamma agonist rosiglitazone attenuated TGF-beta 1-induced extracellular matrix molecule expression and growth factor in PASMCs. These data provide strong evidence that activation of TGF-beta/Smad signaling, via transcriptional suppression of PAR-gamma expression, mediates chronic hypoxia-induced downregulation of PPAR-gamma expression in lung.