title: Short-chain C2 ceramide induces heme oxygenase-1 expression by upregulating AMPK and MAPK signaling pathways in rat primary astrocytes.
abstract: Ceramide belongs to the group of sphingolipid metabolites that are produced in the brain and peripheral systems and act as intracellular second messengers. Although some physiological roles of ceramide have been reported in the brain, the role of ceramide in astrocytes has not been clearly demonstrated. In the present study, we investigated the antioxidant effects of the cell-permeable short-chain C2 ceramide in rat brain astrocytes. C2 ceramide inhibited hydrogen peroxide-induced reactive oxygen species generation and subsequent cell death in rat primary astrocytes. C2 ceramide increased the expression of phase II antioxidant enzymes, such as heme oxygenase-1 (HO-1), NAD(P)H:quinine oxidoreductase 1 (NQO1), and superoxide dismutase (SOD) that are under the control of Nrf2/ARE signaling pathways. Detailed mechanistic studies revealed that C2 ceramide increased the nuclear translocation and DNA binding of nuclear factor-E2-related factor 2 (Nrf2) and c-Jun to the antioxidant response element (ARE), and increased ARE-mediated transcriptional activity. Moreover, C2 ceramide increased the interaction between Nrf2 and c-Jun as shown by antibody co-immunoprecipitation assay. Further analysis of signaling pathways revealed that AMPK and MAP kinases are involved in HO-1 expression by modulating ARE-mediated transcriptional activity. Therefore, the upregulation of antioxidant enzymes by C2 ceramide may be a potential therapeutic modality for neurodegenerative diseases that are accompanied by oxidative stress.
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, South Korea.
authors.forename: Ji-Sun
authors.initials: JS
authors.lastname: Jung
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, South Korea.
authors.forename: Min-Ji
authors.initials: MJ
authors.lastname: Choi
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, South Korea.
authors.forename: Hyun-Myung
authors.initials: HM
authors.lastname: Ko
authors.affiliation: Department of Molecular Medicine and Tissue Injury Defense Research Center, Ewha Womans University Medical School, Seoul, South Korea. Electronic address: hskimp@ewha.ac.kr.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000096:biosynthesis*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D004790:Enzyme Induction / Q000187:drug effects / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis*; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology*
chemical_list: D000975:Antioxidants; D002518:Ceramides; D017382:Reactive Oxygen Species; D006419:Heme Oxygenase (Decyclizing); C491523:Hmox1 protein, rat; D055372:AMP-Activated Protein Kinases
keywords: Astrocyte; C2 ceramide; Heme oxygenase-1; Oxidative stress; Phase II antioxidant enzyme; Signaling mechanism