title: Nitro-fatty acids and cyclopentenone prostaglandins share strategies to activate the Keap1-Nrf2 system: a study using green fluorescent protein transgenic zebrafish.
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-Δ(12,14) -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.
authors.affiliation: 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.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Tsujita
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Hitomi
authors.initials: H
authors.lastname: Nakajima
authors.forename: Noriko
authors.initials: N
authors.lastname: Iwamoto
authors.forename: Yaeko
authors.initials: Y
authors.lastname: Nakajima-Takagi
authors.forename: Ken
authors.initials: K
authors.lastname: Ohashi
authors.forename: Koichi
authors.initials: K
authors.lastname: Kawakami
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Kumagai
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Freeman
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003517:Cyclopentanes; D003545:Cysteine / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids; D049452:Green Fluorescent Proteins / Q000378:metabolism*; D006861:Hydrogen Peroxide / Q000494:pharmacology; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D009829:Oleic Acids / Q000494:pharmacology*; D018384:Oxidative Stress; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D011453:Prostaglandins / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: C521487:10-nitro-oleic acid; C097240:15-deoxy-delta(12,14)-prostaglandin J2; D002352:Carrier Proteins; D003517:Cyclopentanes; D005227:Fatty Acids; C527640:Keap1a protein, zebrafish; D051267:NF-E2-Related Factor 2; D009829:Oleic Acids; D011453:Prostaglandins; D015534:Trans-Activators; D029961:Zebrafish Proteins; D049452:Green Fluorescent Proteins; D006861:Hydrogen Peroxide; D003545:Cysteine; C013905:cyclopentenone; D015230:Prostaglandin D2