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CO Induces Nrf2-Dependent Heme Oxygenase-1 Transcription by Cooperating with Sp1 and c-Jun in Rat Brain Astrocytes

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Abstract

Upregulation of heme oxygenase 1 (HO-1) by carbon monoxide (CO) delivered by CO-releasing molecules (CORMs) may be utilized as a therapeutic intervention for neurodegenerative diseases. This study was to delineate the two putative anti-oxidant response elements (AREs) in modulating HO-1 gene by participating with its promoter elements in rat brain astrocytes (RBA-1). CORM-2-induced HO-1 expression was mediated through superoxide, p38 mitogen-activated protein kinase(MAPK), extracellular signal-regulated protein kinases 1 and 2 (Erk1/2), protein tyrosine kinase 2 (Pyk2), platelet-derived growth factor receptor (PDGFR), and phosphatidylinositol 3'-kinase (PI3K/Akt), revealed by the pharmacological inhibitors or knockdown of these signaling molecules. CORM-2-enhanced HO-1 promoter activity was inhibited by co-transfection with small interfering RNA (siRNA) of c-Jun, specificity protein 1 (Sp1), or nuclear factor-erythroid 2-related factor 2 (Nrf2). Immunoprecipitation assay showed that CORM-2 increased the association of nuclear Nrf2 with Sp1 and c-Jun. Furthermore, chromatin immunoprecipitation (ChIP) assay confirmed that Nrf2, Sp1, and c-Jun are associated with the proximal ARE binding site on HO-1 promoter, suggesting that Nrf2/Sp1/c-Jun cooperations are key transcription factors modulating HO-1 expression. Mechanistically, CORM-2-induced ARE promoter activity was reduced by the inhibitors of reactive oxygen species (ROS), p38 MAPK, Pyk2, MAPK/ERK kinases 1 and 2 (MEK1/2), PDGFR, and PI3K/Akt or the siRNAs of c-Jun, SP1, and Nrf2. These findings suggested that CORM-2 increases formation of c-Jun, Sp1, and Nrf2 complex and binding with ARE1 binding site, which is mediated through both ROS/p38 MAPK and Pyk2-dependent PDGFR/PI3K/Akt/Erk1/2 pathways, resulting in HO-1 expression in RBA-1 cells.

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Acknowledgments

This work was supported by the Ministry of Science and Technology, Taiwan (Grant numbers MOST102-2321-B-182-011 and MOST101-2320-B-182-039-MY3), Chang Gung Medical Research Foundation (Grant numbers CMRPD1C0102, CMRPD1B0383, CMRPD1C0562, CMRPG3B1093, CMRPG3C1302, and CMRPD1B0331), and the Ministry of Education, Taiwan (Grant numbers EMRPD1D0231 and EMRPD1D0241).

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Authors and Affiliations

  1. Department of Physiology and Pharmacology and Health Ageing Research Center, College of Medicine, Chang Gung University, 259 Wen-Hwa 1st Road, Kwei-Shan, 33302, Tao-Yuan, Taiwan

    Pei-Ling Chi, Yu-Wen Chen, Li-Der Hsiao & Chuen-Mao Yang

  2. Department of Anesthetics, Chang Gung Memorial Hospital at Lin-Kou and College of Medicine, Chang Gung University, Kwei-Shan, Tao-Yuan, Taiwan

    Chih-Chung Lin

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  1. Pei-Ling Chi
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Correspondence to Chuen-Mao Yang.

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Pei-Ling Chi and Chih-Chung Lin contributed equally to this work.

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Chi, PL., Lin, CC., Chen, YW. et al. CO Induces Nrf2-Dependent Heme Oxygenase-1 Transcription by Cooperating with Sp1 and c-Jun in Rat Brain Astrocytes. Mol Neurobiol 52, 277–292 (2015). https://doi.org/10.1007/s12035-014-8869-4

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