title: 15-Deoxy-∆12,14-PGJ 2, by activating peroxisome proliferator-activated receptor-gamma, suppresses p22phox transcription to protect brain endothelial cells against hypoxia-induced apoptosis.
abstract: 15-Deoxy-∆(12,14)-PGJ(2) (15d-PGJ(2)) 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-PGJ(2) 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-PGJ(2), 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.
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.forename: Hsin-Da
authors.initials: HD
authors.lastname: Tsai
authors.forename: Chien-Yu
authors.initials: CY
authors.lastname: Huang
authors.forename: Jin-Jer
authors.initials: JJ
authors.lastname: Chen
authors.forename: Teng-Nan
authors.initials: TN
authors.lastname: Lin
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism*; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: C097240:15-deoxy-delta(12,14)-prostaglandin J2; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D015230:Prostaglandin D2