Hypoxia downregulates PPARγ via an ERK1/2-NF-κB-Nox4-dependent mechanism in human pulmonary artery smooth muscle cells.
Hypoxia downregulates PPARγ via an ERK1/2-NF-κB-Nox4-dependent mechanism in human pulmonary artery smooth muscle cells.
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DOI：
10.1016/j.freeradbiomed.2013.05.013
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发表时间：
2013-10
影响因子：
7.4
通讯作者：
Hart, C. M.
中科院分区：
文献类型：
--
作者：
Lu, Xianghuai;Bijli, Kaiser M.;Ramirez, Allan;Murphy, Tamara C.;Kleinhenz, Jennifer;Hart, C. M.
关键词：
配体激活的转录因子，过氧化物酶体增殖物激活受体γ(PPARγ)，调节新陈代谢、细胞增殖和炎症。肺动脉高压(PH)与PPARγ表达降低有关，引起PH的低氧暴露可降低PPARγ的表达。本研究在体外和体内研究了低氧诱导PPARγ下调的机制。低氧可降低人肺动脉平滑肌细胞PPARγ基因和蛋白水平、PPARγ活性和PPARγ调控基因的表达。同样，小鼠暴露于低氧(10%O2)3周后，肺组织中PPARPPARγ的基因和蛋白表达减少。用PD98059抑制ERK1/2或用针对NF-κB p65或NOX4的siRNA处理均可减轻缺氧性PPARγ表达和活性的降低。此外，利用聚乙二醇过氧化氢酶降解过氧化氢可以阻止缺氧诱导的ERK 1/2磷酸化和NOX4的表达，这表明ERK 1/2介导的信号和NOX4在这一反应中持续表达。哺乳动物双杂交实验表明，PPARγ和P65以相互抑制的方式直接结合。综上所述，我们得出的结论是，促进PH发病和HPASMC增殖的低氧方案通过依赖ERK1/2、P65和NOX4的途径降低PPARγ的表达和活性。这些发现对低氧等病理生理刺激导致PPARγ活性丧失和肺血管细胞增殖、肺血管重构和肺高压的机制提供了新的见解。这些结果还表明，用药理配体恢复PPARγ活性可能为某些类型的PH提供一种新的治疗方法。
The ligand-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ), regulates metabolism, cell proliferation, and inflammation. Pulmonary hypertension (PH) is associated with reduced PPARγ expression, and hypoxia exposure regimens that cause PH reduce PPARγ expression. The current study examines mechanisms of hypoxia-induced PPARγ downregulation in vitro and in vivo. Hypoxia reduced PPARγ mRNA and protein levels, PPARγ activity, and the expression of PPARγ regulated genes in human pulmonary artery smooth muscle cells (HPASMC) exposed to 1% oxygen for 72 hours. Similarly, exposure of mice to hypoxia (10% O2) for 3 weeks reduced PPARγ mRNA and protein in mouse lung. Inhibiting ERK1/2 with PD98059 or treatment with siRNA directed against either NF-κB p65 or Nox4 attenuated hypoxic reductions in PPARγ expression and activity. Furthermore, degradation of H2O2 using PEG-catalase prevented hypoxia-induced ERK 1/2 phosphorylation and Nox4 expression suggesting sustained ERK 1/2-mediated signaling and Nox4 expression in this response. Mammalian two hybrid assays demonstrated that PPARγ and p65 bind directly to each other in a mutually repressive fashion. Taken together, we conclude that hypoxic regimens that promote PH pathogenesis and HPASMC proliferation reduce PPARγ expression and activity through ERK1/2-, p65-, and Nox4-dependent pathways. These findings provide novel insights into mechanisms by which pathophysiological stimuli such as hypoxia cause loss of PPARγ activity and pulmonary vascular cell proliferation, pulmonary vascular remodeling, and PH. These results also indicate that restoration of PPARγ activity with pharmacological ligands may provide a novel therapeutic approach in selected forms of PH.
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DOI：
10.1073/pnas.251194298
发表时间：
2001-11-20
影响因子：
11.1
作者：
Bennett, BL;Sasaki, DT;Anderson, DW
通讯作者：
Anderson, DW
DOI：
10.1152/ajplung.00258.2006
发表时间：
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影响因子：
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影响因子：
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作者：
Gong, Kaizheng;Xing, Dongqi;Chen, Yiu-Fai
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影响因子：
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作者：
Hansmann, Georg;de Jesus Perez, Vinicio A.;Rabinovitch, Marlene
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Rabinovitch, Marlene
DOI：
10.1152/ajplung.00090.2010
发表时间：
2010-10-01
影响因子：
4.9
作者：
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