Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keap1-Nrf2 system: a study using green fluorescent protein transgenic zebrafish

Authors

  • Tadayuki Tsujita,

    1. Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Center for TARA, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
    2. ERATO Environmental Response Project, Japan Science and Technology Agency, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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    • Communicated by: Kohei Miyazono

  • Li Li,

    1. Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Center for TARA, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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    • Communicated by: Kohei Miyazono

  • Hitomi Nakajima,

    1. Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Center for TARA, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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  • Noriko Iwamoto,

    1. Institute of Community Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
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  • Yaeko Nakajima-Takagi,

    1. Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Center for TARA, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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  • Ken Ohashi,

    1. Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Center for TARA, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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  • Koichi Kawakami,

    1. Division of Molecular and Developmental Biology, National Institute of Genetics, and Department of Genetics, Graduate University for Advanced Studies (SOKENDAI), 1111 Yata, Mishima 411-8570, Japan
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  • Yoshito Kumagai,

    1. Institute of Community Medicine, Graduate School of Comprehensive Human Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8575, Japan
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  • Bruce A. Freeman,

    1. Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA
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  • Masayuki Yamamoto,

    1. ERATO Environmental Response Project, Japan Science and Technology Agency, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
    2. Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan
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  • Makoto Kobayashi

    Corresponding author
    1. Institute of Basic Medical Sciences, Graduate School of Comprehensive Human Sciences, Center for TARA, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
    2. ERATO Environmental Response Project, Japan Science and Technology Agency, University of Tsukuba, 1-1-1 Tennodai, Tsukuba 305-8577, Japan
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  • These authors equally contributed to this work.

makobayash@md.tsukuba.ac.jp

Abstract

Nitro-fatty acids are electrophilic fatty acids produced in vivo from nitrogen peroxide that have many physiological activities. We recently demonstrated that nitro-fatty acids activate the Keap1-Nrf2 system, which protects cells from damage owing to electrophilic or oxidative stresses via transactivating an array of cytoprotective genes, although the molecular mechanism how they activate Nrf2 is unclear. A number of chemical compounds with different structures have been reported to activate the Keap1-Nrf2 system, which can be categorized into at least six classes based on their sensing pathways. In this study, we showed that nitro-oleic acid (OA-NO2), one of major nitro-fatty acids, activates Nrf2 in the same manner that of a cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) using transgenic zebrafish that expresses green fluorescent protein (GFP) in response to Nrf2 activators. In transgenic embryos, GFP was induced in the whole body by treatment with OA-NO2, 15d-PGJ2 or diethylmaleate (DEM), but not with hydrogen peroxide (H2O2), when exogenous Nrf2 and Keap1 were co-overexpressed. Induction by OA-NO2 or 15d-PGJ2 but not DEM was observed, even when a C151S mutation was introduced in Keap1. Our results support the contention that OA-NO2 and 15d-PGJ2 share an analogous cysteine code as electrophiles and also have similar anti-inflammatory roles.

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