title: PPAR-γ Ameliorates Neuronal Apoptosis and Ischemic Brain Injury via Suppressing NF-κB-Driven p22phox Transcription.
abstract: Peroxisome proliferator-activated receptor-gamma (PPAR-γ), a stress-induced transcription factor, protects neurons against ischemic stroke insult by reducing oxidative stress. NADPH oxidase (NOX) activation, a major driving force in ROS generation in the setting of reoxygenation/reperfusion, constitutes an important pathogenetic mechanism of ischemic brain damage. In the present study, both transient in vitro oxygen-glucose deprivation and in vivo middle cerebral artery (MCA) occlusion-reperfusion experimental paradigms of ischemic neuronal death were used to investigate the interaction between PPAR-γ and NOX. With pharmacological (PPAR-γ antagonist GW9662), loss-of-function (PPAR-γ siRNA), and gain-of-function (Ad-PPAR-γ) approaches, we first demonstrated that 15-deoxy-∆(12,14)-PGJ2 (15d-PGJ2), via selectively attenuating p22phox expression, inhibited NOX activation and the subsequent ROS generation and neuronal death in a PPAR-γ-dependent manner. Secondly, results of promoter analyses and subcellular localization studies further revealed that PPAR-γ, via inhibiting hypoxia-induced NF-κB nuclear translocation, indirectly suppressed NF-κB-driven p22phox transcription. Noteworthily, postischemic p22phox siRNA treatment not only reduced infarct volumes but also improved functional outcome. In summary, we report a novel transrepression mechanism involving PPAR-γ downregulation of p22phox expression to suppress the subsequent NOX activation, ischemic neuronal death, and brain infarct. Identification of a PPAR-γ → NF-κB → p22phox neuroprotective signaling cascade opens a new avenue for protecting the brain against ischemic insult.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Rm 404, Taipei, 11529, Taiwan, Republic of China.
authors.forename: Jui-Sheng
authors.initials: JS
authors.lastname: Wu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Rm 404, Taipei, 11529, Taiwan, Republic of China.
authors.forename: Hsin-Da
authors.initials: HD
authors.lastname: Tsai
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Rm 404, Taipei, 11529, Taiwan, Republic of China.
authors.forename: Wai-Mui
authors.initials: WM
authors.lastname: Cheung
authors.affiliation: Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan.
authors.forename: Chung Y
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Rm 404, Taipei, 11529, Taiwan, Republic of China. bmltn@ibms.sinica.edu.tw.|Institute of Neuroscience, National Yang-Ming University, Taipei, Taiwan. bmltn@ibms.sinica.edu.tw.|Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan. bmltn@ibms.sinica.edu.tw.
authors.forename: Teng-Nan
authors.initials: TN
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D002545:Brain Ischemia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000473:pathology; D002544:Cerebral Infarction / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D003573:Cytochrome b Group / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000172:deficiency; D008297:Male; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D010084:Oxidation-Reduction; D010100:Oxygen; D047495:PPAR gamma / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015230:Prostaglandin D2 / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D020318:Rats, Long-Evans; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C477819:15-deoxyprostaglandin J2; D003573:Cytochrome b Group; D016328:NF-kappa B; D047495:PPAR gamma; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; C515614:Cyba protein, mouse; D005947:Glucose; D015230:Prostaglandin D2; D010100:Oxygen
keywords: Gene regulation; NADPH oxidase; NF-κB; Nox2