title: trans-Fatty acids promote proinflammatory signaling and cell death by stimulating the apoptosis signal-regulating kinase 1 (ASK1)-p38 pathway.
abstract: Food-bornetrans-fatty acids (TFAs) are mainly produced as byproducts during food manufacture. Recent epidemiological studies have revealed that TFA consumption is a major risk factor for various disorders, including atherosclerosis. However, the underlying mechanisms in this disease etiology are largely unknown. Here we have shown that TFAs potentiate activation of apoptosis signal-regulating kinase 1 (ASK1) induced by extracellular ATP, a damage-associated molecular pattern leaked from injured cells. Major food-associated TFAs such as elaidic acid (EA), linoelaidic acid, andtrans-vaccenic acid, but not their correspondingcisisomers, dramatically enhanced extracellular ATP-induced apoptosis, accompanied by elevated activation of the ASK1-p38 pathway in a macrophage-like cell line, RAW264.7. Moreover, knocking out the ASK1-encoding gene abolished EA-mediated enhancement of apoptosis. We have reported previously that extracellular ATP induces apoptosis through the ASK1-p38 pathway activated by reactive oxygen species generated downstream of the P2X purinoceptor 7 (P2X7). However, here we show that EA did not increase ATP-induced reactive oxygen species generation but, rather, augmented the effects of calcium/calmodulin-dependent kinase II-dependent ASK1 activation. These results demonstrate that TFAs promote extracellular ATP-induced apoptosis by targeting ASK1 and indicate novel TFA-associated pathways leading to inflammatory signal transduction and cell death that underlie the pathogenesis and progression of TFA-induced atherosclerosis. Our study thus provides insight into the pathogenic mechanisms of and proposes potential therapeutic targets for these TFA-related disorders.
authors.affiliation: Laboratory of Health Chemistry.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Hirata
authors.affiliation: Laboratory of Health Chemistry.
authors.forename: Miki
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Laboratory of Health Chemistry.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kudoh
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology, Chiyoda-ku, 100-0004 Tokyo, Japan.
authors.forename: Kuniyuki
authors.initials: K
authors.lastname: Kano
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Kawana
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Makide
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, 980-8578 Sendai, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Shinoda
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, 980-8578 Sendai, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yabuki
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3, Aoba, Aramaki, Aoba-ku, 980-8578 Sendai, Japan.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
authors.affiliation: Laboratory of Molecular and Cellular Biochemistry; Japan Agency for Medical Research and Development, Core Research for Evolutional Science and Technology, Chiyoda-ku, 100-0004 Tokyo, Japan.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Laboratory of Health Chemistry. Electronic address: noguchi@m.tohoku.ac.jp.
authors.forename: Takuya
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Laboratory of Health Chemistry. Electronic address: matsushi@m.tohoku.ac.jp.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D050197:Atherosclerosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048848:MAP Kinase Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D051379:Mice; D000067996:RAW 264.7 Cells; D017382:Reactive Oxygen Species / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000235:genetics / Q000378:metabolism; D044242:Trans Fatty Acids / Q000009:adverse effects* / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D058486:Receptors, Purinergic P2X7; D044242:Trans Fatty Acids; D000255:Adenosine Triphosphate; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; C482859:Map3k5 protein, mouse
keywords: P2X7; apoptosis; apoptosis signal-regulating kinase 1 (ASK1); macrophage; p38 MAPK