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Arachidonic Acid Induces ARE/Nrf2-Dependent Heme Oxygenase-1 Transcription in Rat Brain Astrocytes

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Abstract

Arachidonic acid (AA) is a major product of phospholipid hydrolysis catalyzed by phospholipase A2 during neurodegenerative diseases. AA exerts as a second messenger to regulate various signaling components which may be involved in different pathophysiological processes. Astrocytes are the main types of CNS resident cells which maintain and support the physiological function of brain. AA has been shown to induce ROS generation through activation of NADPH oxidases (Noxs) which may play a key role in the expression of heme oxygenase-1 (HO-1). Therefore, this study was designed to investigate the mechanisms underlying AA-induced HO-1 expression in rat brain astrocytes (RBA-1). We found that AA induced HO-1 protein and mRNA expression and promoter activity in RBA-1, which was mediated through the synthesis of 15-deoxy-Δ12,14-prostaglandin D2-activated peroxisome proliferator-activated receptor-γ (PPARγ) receptors. This note was confirmed by transfection with PPARγ small interfering RNAs (siRNA) which attenuated the AA-mediated responses. AA-induced HO-1 expression was mediated through Nox/ROS generation, which was inhibited by Nox inhibitors (diphenyleneiodonium and apocynin) and ROS scavengers (N-acetyl cysteine). Moreover, AA-induced HO-1 expression was mediated through phosphorylation of Src, Pyk2, platelet-derived growth factor, PI3K/Akt, and ERK1/2 which were inhibited by the pharmacological inhibitors including PP1, PF431396, AG1296, LY294002, and U0126 or by transfection with respective siRNAs. AA-enhanced Nrf2 expression and HO-1 promoter activity was inhibited by transfection with Nrf2 siRNA or by these pharmacological inhibitors. Furthermore, chromatin immunoprecipitation assay confirmed that Nrf2 and PPARγ were associated with the proximal antioxidant response element (ARE)-binding site on HO-1 promoter, suggesting that Nrf2/PPARγ are key transcription factors modulating HO-1 expression. AA-induced ARE promoter activity was also reduced by these pharmacological inhibitors. These findings suggested that AA increases formation of Nrf2 and PPARγ complex and binding with ARE1 binding site through Src, Pyk2, PI3K/Akt, and ERK1/2, which further induced HO-1 expression in RBA-1 cells.

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Acknowledgements

This work was supported by the Ministry of Science and Technology, Taiwan (Grant numbers MOST104-2320-B-182A-003-MY3, MOST104-2320-B-182-010, and MOST105-2320-B-182-005-MY3); Chang Gung Medical Research Foundation (Grant numbers CMRPD1F0022, CMRPD1F0023, CMRPD1F0511, CMRPD1F0512, CMRPG3E2232, CMRPG3F1531, CMRPG3F1532, CMRPG5F0201, and CMRPG5F0201); and the Ministry of Education, Taiwan (Grant numbers EMRPD1G0171 and EMRPD1G0281).

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  1. Chih-Chung Lin and Chien-Chung Yang contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthetics, Chang Gung Memorial Hospital at Linkou, and College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan

    Chih-Chung Lin, Li-Der Hsiao & Chuen-Mao Yang

  2. Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital, Linkou, Kwei-San, Tao-Yuan, Taiwan

    Chien-Chung Yang

  3. Department of Physiology and Pharmacology and Health Aging Research Center, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, Taiwan

    Chien-Chung Yang, Yu-Wen Chen & Chuen-Mao Yang

  4. Research Center for Industry of Human Ecology, Research Center for Chinese Herbal Medicine, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Tao-Yuan, Taiwan

    Chuen-Mao Yang

  5. Department of Physiology and Pharmacology, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, Taiwan

    Chuen-Mao Yang

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Lin, CC., Yang, CC., Chen, YW. et al. Arachidonic Acid Induces ARE/Nrf2-Dependent Heme Oxygenase-1 Transcription in Rat Brain Astrocytes. Mol Neurobiol 55, 3328–3343 (2018). https://doi.org/10.1007/s12035-017-0590-7

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