12,14-PGJ2 (15d-PGJ2) and thiazolidinedione attenuate reactive oxygen species (ROS) production via a peroxisome proliferator-activated receptor-gamma (PPAR-γ)-dependent pathway. Nonetheless, how PPAR-γ mediates ROS production to ameliorate ischemic brain injury is not clear. Recent studies indicated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in the vascular system. In the present study, we used an in vitro oxygen–glucose deprivation and reoxygenation (hypoxia reoxygenation [HR]) paradigm to study whether PPAR-γ interacts with NADPH oxidase, thereby regulating ROS formation in cerebral endothelial cells (CECs). With pharmacological (PPAR-γ antagonist GW9662), loss-of-function (PPAR-γ siRNA), and gain-of-function (Ad-PPAR-γ) approaches, we first demonstrated that 15d-PGJ2 protected HR-treated CECs against ROS-induced apoptosis in a PPAR-γ-dependent manner. Results of promoter and subcellular localization analyses further revealed that 15d-PGJ2, by activating PPAR-γ, blocked HR-induced NF-κB nuclear translocation, which led to inhibited transcription of the NADPH oxidase subunit p22phox. In summary, we report a novel transrepression mechanism whereby PPAR-γ downregulates hypoxia-activated p22phox transcription and the subsequent NADPH oxidase activation, ROS formation, and CEC apoptosis." />
15-Deoxy-?sup class="a-plus-plus">12,14-PGJ2, by Activating Peroxisome Proliferator-Activated Receptor-Gamma, Suppresses p22phox Transcription to Protect Brain Endothelial Cells Against Hypoxia-Induced Apoptosis
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  • 作者：Jui-Sheng Wu ; Hsin-Da Tsai ; Chien-Yu Huang ; Jin-Jer Chen…
  • 关键词：Gene regulation ; Nox2 ; NF ; κB ; Superoxide dismutase 1 ; Oxygen–glucose deprivation
  • 刊名：Molecular Neurobiology
  • 出版年：2014
  • 出版时间：August 2014
  • 年：2014
  • 卷：50
  • 期：1
  • 页码：221-238
  • 全文大小：5,165 KB
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  • 作者单位：Jui-Sheng Wu (1)
    Hsin-Da Tsai (1) (2)
    Chien-Yu Huang (1)
    Jin-Jer Chen (1)
    Teng-Nan Lin (1) (2) (3)

    1. Institute of Biomedical Sciences, Academia Sinica, Rm 404, Taipei, 11529, Taiwan, Republic of China
    2. Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan, Republic of China
    3. Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan, Republic of China
  • ISSN：1559-1182
文摘
15-Deoxy-?sup class="a-plus-plus">12,14-PGJ2 (15d-PGJ2) and thiazolidinedione attenuate reactive oxygen species (ROS) production via a peroxisome proliferator-activated receptor-gamma (PPAR-γ)-dependent pathway. Nonetheless, how PPAR-γ mediates ROS production to ameliorate ischemic brain injury is not clear. Recent studies indicated that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is the major source of ROS in the vascular system. In the present study, we used an in vitro oxygen–glucose deprivation and reoxygenation (hypoxia reoxygenation [HR]) paradigm to study whether PPAR-γ interacts with NADPH oxidase, thereby regulating ROS formation in cerebral endothelial cells (CECs). With pharmacological (PPAR-γ antagonist GW9662), loss-of-function (PPAR-γ siRNA), and gain-of-function (Ad-PPAR-γ) approaches, we first demonstrated that 15d-PGJ2 protected HR-treated CECs against ROS-induced apoptosis in a PPAR-γ-dependent manner. Results of promoter and subcellular localization analyses further revealed that 15d-PGJ2, by activating PPAR-γ, blocked HR-induced NF-κB nuclear translocation, which led to inhibited transcription of the NADPH oxidase subunit p22phox. In summary, we report a novel transrepression mechanism whereby PPAR-γ downregulates hypoxia-activated p22phox transcription and the subsequent NADPH oxidase activation, ROS formation, and CEC apoptosis.

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